Spiro compounds as inhibitors of KRAS

ABSTRACT

Disclosed are spirocyclic compounds of Formula I, methods of using the compounds for inhibiting KRAS activity and treating cancer, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with KRAS activity such as cancer.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/963,467 filed on Jan. 20, 2020, the entire content of which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The disclosure provides compounds as well as their compositions andmethods of use. The compounds modulate KRAS activity and are useful inthe treatment of various diseases including cancer.

BACKGROUND OF THE INVENTION

Ras proteins are part of the family of small GTPases that are activatedby growth factors and various extracellular stimuli. The Ras familyregulates intracellular signaling pathways responsible for growth,migration, survival and differentiation of cells. Activation of RASproteins at the cell membrane results in the binding of key effectorsand initiation of a cascade of intracellular signaling pathways withinthe cell, including the RAF and PI3K kinase pathways. Somatic mutationsin RAS may result in uncontrolled cell growth and malignanttransformation while the activation of RAS proteins is tightly regulatedin normal cells (Simanshu, D. et al. Cell 170.1 (2017):17-33).

The Ras family is comprised of three members: KRAS, NRAS and HRAS. RASmutant cancers account for about 25% of human cancers. KRAS is the mostfrequently mutated isoform accounting for 85% of all RAS mutationswhereas NRAS and HRAS are found mutated in 12% and 3% of all Ras mutantcancers respectively (Simanshu, D. et al. Cell 170.1 (2017):17-33). KRASmutations are prevalent amongst the top three most deadly cancer types:pancreatic (97%), colorectal (44%), and lung (30%) (Cox, A. D. et al.Nat Rev Drug Discov (2014) 13:828-51). The majority of RAS mutationsoccur at amino acid residue 12, 13, and 61. The frequency of specificmutations varies between RAS gene isoforms and while G12 and Q61mutations are predominant in KRAS and NRAS respectively, G12, G13 andQ61 mutations are most frequent in HRAS. Furthermore, the spectrum ofmutations in a RAS isoform differs between cancer types. For example,KRAS G12D mutations predominate in pancreatic cancers (51%), followed bycolorectal adenocarcinomas (45%) and lung cancers (17%) while KRAS G12 Vmutations are associated with pancreatic cancers (30%), followed bycolorectal adenocarcinomas (27%) and lung adenocarcinomas (23%) (Cox, A.D. et al. Nat Rev Drug Discov (2014) 13:828-51). In contrast, KRAS G12Cmutations predominate in non-small cell lung cancer (NSCLC) comprising11-16% of lung adenocarcinomas, and 2-5% of pancreatic and colorectaladenocarcinomas (Cox, A. D. et al. Nat. Rev. Drug Discov. (2014)13:828-51). Genomic studies across hundreds of cancer cell lines havedemonstrated that cancer cells harboring KRAS mutations are highlydependent on KRAS function for cell growth and survival (McDonald, R. etal. Cell 170 (2017): 577-592). The role of mutant KRAS as an oncogenicdriver is further supported by extensive in vivo experimental evidenceshowing mutant KRAS is required for early tumour onset and maintenancein animal models (Cox, A. D. et al. Nat Rev Drug Discov (2014)13:828-51).

Taken together, these findings suggest that KRAS mutations play acritical role in human cancers; development of inhibitors targetingmutant KRAS may therefore be useful in the clinical treatment ofdiseases that are characterized by a KRAS mutation.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present disclosure further provides a pharmaceutical compositioncomprising a compound of the disclosure, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient.

The present disclosure further provides methods of inhibiting KRASactivity, which comprises administering to an individual a compound ofthe disclosure, or a pharmaceutically acceptable salt thereof. Thepresent disclosure also provides uses of the compounds described hereinin the manufacture of a medicament for use in therapy. The presentdisclosure also provides the compounds described herein for use intherapy.

The present disclosure further provides methods of treating a disease ordisorder in a patient comprising administering to the patient atherapeutically effective amount of a compound of the disclosure, or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION

Compounds

In an aspect, provided herein is a compound of Formula I:

-   -   or a pharmaceutically acceptable salt thereof,    -   wherein:    -   represents a single bond or a double bond;    -   X is N or CR⁷;    -   Y is O, NR^(5N), C═O, or C(R⁵)₂;    -   W is C═O, or C(R⁸)₂;    -   Z is O, NR^(9N), C(R⁹)₂, or a bond;    -   R¹ is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a1),        SR^(a1), C(O)R^(1b), C(O)NR^(c1)R^(d1), C(O)OR^(a1),        OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),        NR^(c1)C(O)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),        NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),        NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1),        S(O)₂R^(b1), S(O)₂NR^(c1)R^(d1), and BR^(h1)R^(i1); wherein said        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl,        5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, are        each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R^(g);    -   R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a2), SR^(a2),        C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),        OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(d2),        NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),        C(═NOR^(a2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),        NR²C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))R^(b2),        NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),        NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2),        S(O)₂R^(b2), S(O)₂NR^(c2)R^(d2), and BR^(h2)R^(i2); wherein said        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and        5-10 membered heteroaryl-C₁₋₃ alkylene are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R²⁰;    -   Cy is selected from C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;        wherein the 4-10 membered heterocycloalkyl and 5-10 membered        heteroaryl each has at least one ring-forming carbon atom and 1,        2, 3, or 4 ring-forming heteroatoms independently selected from        N, O, and S; wherein the N and S are optionally oxidized;        wherein a ring-forming carbon atom of 5-10 membered heteroaryl        and 4-10 membered heterocycloalkyl is optionally substituted by        oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl are each optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹⁰;    -   when R³N        CR⁴ is a single bond, then R⁴ is selected from ═O and ═S; and    -   R³ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10 membered        heteroaryl-C₁₋₃ alkylene; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃        alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀        aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene        are each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R³⁰;    -   when R³N        CR⁴ is a double bond, then R³ is absent; and    -   R⁴ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a3), SR^(a3),        C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),        OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),        NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),        C(═NOR^(a3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),        NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))R^(b3),        NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3),        NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3), S(O)NR^(c3)R^(d3),        S(O)₂R^(b3), S(O)₂NR^(c3)R^(d3), and BR^(h3)R^(i3); wherein said        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and        5-10 membered heteroaryl-C₁₋₃ alkylene are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R³⁰;    -   R^(5N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10 membered        heteroaryl-C₁₋₃ alkylene; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃        alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀        aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene        are each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁵⁰;    -   each R⁵ and R⁸ are independently selected from H, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a5),        SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), (O)OR^(a5), OC(O)R^(b5),        OC(O)NR^(c5)R^(d5), NR^(c5)R^(5d), NR^(c5)C(O)R^(b5),        NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),        C(═NOR^(a5))R^(b5), C(═NR^(e5))NR^(c5)R^(d5),        NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e5))R^(b5),        NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),        NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),        S(O)₂R^(b5), S(O)₂NR^(c5)R^(d5), and BR^(h5)R^(i5); wherein said        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and        5-10 membered heteroaryl-C₁₋₃ alkylene are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁵⁰;    -   ring A is selected from C₃₋₁₀ cycloalkyl and 4-14 membered        heterocycloalkyl; wherein the 4-14 membered heterocycloalkyl has        at least one ring-forming carbon atom and 1, 2, 3, or 4        ring-forming heteroatoms independently selected from N, O, and        S; wherein the N and S are optionally oxidized; wherein a        ring-forming carbon atom of 4-14 membered heterocycloalkyl is        optionally substituted by oxo to form a carbonyl group;    -   n is 0, 1, 2, 3, or 4;    -   each R⁶ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a6), SR^(a6),        C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),        OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),        NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6), C(═NR^(e6))R^(b6),        C(═NOR^(a6))R^(b6), C(═NR^(e6))NR^(c6)R^(d6),        NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), NR^(c6)C(═NR^(e6))R^(b6),        NR^(c6)S(O)R^(b6), NR⁶S(O)₂R^(b6), NR⁶S(O)₂NR^(c6)R^(d6),        S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), S(O)₂NR^(c6)R^(d6),        and BR^(h6)R^(i6); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁶⁰;    -   R⁷ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a7), SR^(a7),        C(O)R^(b7), C(O)NR^(c7)R^(d7), (O)OR^(a7), OC(O)R^(b7),        OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),        NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), C(═NR^(e7))R^(b7),        C(═NOR^(a7))R^(b7), C(═NR^(e7))NR^(c7)R^(d7),        NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(e7))R^(b7),        NR^(c7)S(O)R^(b7), NR^(c7)S(O)₂R^(b7), NR⁷S(O)₂NR^(c7)R^(d7),        S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), S(O)₂NR^(c7)R^(d7),        and BR^(h7)R^(i7); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁷⁰;    -   R^(9N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, and 4-7 membered heterocycloalkyl; wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6        membered heteroaryl, and 4-7 membered heterocycloalkyl, are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R^(g);    -   each R⁹ is independently selected from selected from H, D, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆        cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, halo, CN, OR^(a9), SR^(a9), C(O)R^(b9),        C(O)NR^(c9)R^(d9), (O)OR^(a9), OC(O)R^(b9), OC(O)NR^(c9)R^(d9),        NR^(c9)R^(d9), NR^(c9)C(O)R^(b9), NR^(c9)C(O)OR^(a9),        NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9), NR^(c9)S(O)₂R^(b9),        NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9), S(O)NR^(c9)R^(d9),        S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), and BR^(h9)R^(i9); wherein said        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl,        5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, are        each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R^(g);    -   each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a10),        SR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10),        C(O)OR^(a10)(O)R^(b10), OC(O)NR^(c10)R^(d10), NR^(c10)R^(d10),        NR^(c10), C(O)R^(b10), NR^(c10), C(O)OR^(a10), NR^(c10),        C(O)NR^(c10)R^(d10)C(═NR^(e10))R^(b10), C(═NOR^(a10))R^(b10),        C(═NR^(e10))NR^(c10)R^(d10),        NR^(c10)C(═NR^(e10))NR^(c10)R^(d10),        NR^(c10)C(═NR^(e10))R^(b10), NR^(c10)S(O)R^(b10),        NR^(c10)S(O)₂R^(b10), NR^(c10)S(O)₂NR^(c10)R^(d10), S(O)R^(b10),        S(O)NR^(c10)R^(d10), S(O)₂R^(b10), S(O)₂NR^(c10)R^(d10), and        BR^(h10)R^(i10); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R¹¹;    -   each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a11),        SR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11),        OC(O)R^(b11), OC(O)NR^(c11)R^(d11), NR^(c11)R^(d11),        NR¹¹C(O)R^(b11), NR^(c11)C(O)OR^(a11),        NR^(c11)C(O)NR^(c11)R^(d11), NR^(c11)S(O)R^(b11),        NR^(c11)S(O)₂R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11), S(O)R^(b11),        S(O)NR^(c11)R^(d11), S(O)₂R^(b11), S(O)₂NR^(c11)R^(d11), and        BR^(h11)R^(i11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R¹²;    -   each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,        CN, OR^(a12), SR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12),        C(O)OR^(a12), OC(O)R^(b12), OC(O)NR^(c12)R^(d12),        NR^(c12)R^(d12), NR^(c12)C(O)R^(b12), NR^(c12)C(O)OR^(a12),        NR^(c12)C(O)NR^(c12)R^(d12), NR^(c12)S(O)R^(b12),        NR^(c12)S(O)₂R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12), S(O)R^(b12),        S(O)NR^(c12)R^(d12), S(O)₂R^(b12), S(O)₂NR^(c12)R^(d12), and        BR^(h12)R^(i12); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and        4-7 membered heterocycloalkyl, are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        R^(g);    -   each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a20),        SR^(a20), C(O)R^(b20), C(O)NR^(c20)R^(d20), (O)OR^(a2),        OC(O)R^(b20), OC(O)NR^(c20)R^(d20), NR^(c20)R^(d20), NR^(c20),        C(O)R^(b20), NR^(c20), C(O)OR^(a2), NR^(c20),        C(O)NR^(c2)R^(d20), NR^(c20)S(O)R^(b20), NR^(c20)S(O)₂R^(b20),        NR^(c20)S(O)₂NR^(c20)R^(d20), S(O)R^(b20), S(O)NR^(c20)R^(d20),        S(O)₂R^(b20), S(O)₂NR^(c20)R^(d20), and BR^(h20)R^(i20); wherein        said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and        5-10 membered heteroaryl-C₁₋₃ alkylene are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R²¹;    -   each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a21),        SR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),        OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(c21)R^(d21),        NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21),        NR^(c21)C(O)NR^(c21)R^(d21), NR^(c21)S(O)R^(b21),        NR^(c21)S(O)₂R^(b21), NR^(c21)S(O)₂NR^(c21)R^(d21), S(O)R^(b21),        S(O)NR^(c21)R^(d21), S(O)₂R^(b21), S(O)₂NR^(c21)R^(d21), and        BR^(h21)R^(i21); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R²²;    -   each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,        CN, OR^(a22), SR^(a22), C(O)R^(b22), C(O)NR^(c22)R^(d22),        C(O)OR^(a22), OC(O)R^(b22), OC(O)NR^(c22)R^(d22),        NR^(c22)R^(d22), NR^(c22)C(O)R^(b22), NR^(c22)C(O)OR^(a22),        NR^(c22)C(O)NR^(c22)R^(d22), NR^(c22)S(O)R^(b22),        NR^(c22)S(O)₂R^(b22), NR^(c22)S(O)₂NR^(c22)R^(d22), S(O)R^(b22),        S(O)NR^(c22)R^(d22), S(O)₂R^(b22), S(O)₂NR^(c22)R^(d22), and        BR^(h22)R^(i22); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and        4-7 membered heterocycloalkyl, are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        R^(g);    -   each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a30),        SR^(a30), C(O)R^(b30), C(O)NR^(c30)R^(d30), C(O)OR^(a30),        OC(O)R^(b30), OC(O)NR^(c30)R^(d30), NR^(c30)R^(d30),        NR^(c30)C(O)R^(b30), NR^(c30)C(O)OR^(a30),        NR^(c30)C(O)NR^(c30)R^(d30), C(═NR^(e30))R^(b30),        C(═NOR^(a30))R^(b30), C(═NR^(e30))NR^(c30)R^(d30),        NR^(c30)C(═NR^(e30))NR^(c30)R^(d30),        NR^(c30)C(═NR^(e30))R^(b30), NR^(c30)S(O)R^(b30),        NR^(c30)S(O)₂R^(b30), NR^(c30)S(O)₂NR^(c30)R^(d30), S(O)R^(b30),        S(O)NR^(c30)R^(d30), S(O)₂R^(b30), S(O)₂NR^(c30)R^(d30), and        BR^(h30)R^(i30); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R³¹;    -   each R³¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a31),        SR^(a31), C(O)R^(b31), C(O)NR^(c31)R^(d31),        C(O)OR^(a31)OC(O)R^(b31), OC(O)NR^(c31)R^(d31), NR^(c31)R^(d31),        NR^(c31)C(O)R^(b31), NR^(c1)C(O)OR^(a31),        NR^(c1)C(O)NR^(c1)R^(d31), NR^(c1)S(O)R^(b31), NR³¹S(O)₂R^(b31),        NR^(c31)S(O)₂NR^(c31)R^(d31), S(O)R^(b31), S(O)NR^(c31)R^(d31),        S(O)₂R^(b31), S(O)₂NR^(c31)R^(d31), and BR^(h31)R^(i31); wherein        said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and        5-10 membered heteroaryl-C₁₋₃ alkylene are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R³²;    -   each R³² is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,        CN, OR^(a32), SR^(a32), C(O)R^(b32), C(O)NR^(c32)R^(d32),        C(O)OR^(a32), OC(O)R^(b32), OC(O)NR^(c32)R^(d32),        NR^(c32)R^(d32), NR^(c32)C(O)R^(d32), NR^(c2)C(O)OR^(a32),        NR^(c32)C(O)NR^(c32)R^(d32), NR^(c2)S(O)R^(b32),        NR^(c32)S(O)₂R^(b32), NR³²S(O)₂NR^(c32)R^(d32), S(O)R^(b32),        S(O)NR^(c32)R^(d32), S(O)₂R^(b32), S(O)₂NR^(c32)R^(d32), and        BR^(h32)R^(i32); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl, are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        R^(g);    -   each R⁵⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a50),        SR^(a50), C(O)R^(b50), C(O)NR^(c50)R^(d50), C(O)OR^(a50),        OC(O)R^(b50), OC(O)NR^(c50)R^(d50), NR^(c50)R^(d50),        NR^(c50)C(O)R^(b50), NR^(c50)C(O)OR^(a50),        NR^(c50)C(O)NR^(d50)R^(d50), NR^(c50), S(O)R^(b50),        NR^(c50)S(O)₂R^(b50), NR^(c50)S(O)₂NR^(c50)R^(d50), S(O)R^(b50),        S(O)NR^(c5)R^(d50), S(O)₂R^(b50), S(O)₂NR^(c50)R^(d50), and        BR^(h50)R^(i50); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁵¹;    -   each R⁵¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a51),        SR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51), C(O)OR^(a51),        OC(O)R^(b51), OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51),        NR⁵¹C(O)R^(b51), NR^(c51)C(O)OR^(a51), NR⁵¹C(O)NR^(c51)R^(d51),        NR^(c51)S(O)R^(b51), NR^(c51)S(O)₂R^(b51),        NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)R^(b51), S(O)NR^(c51)R^(d51),        S(O)₂R^(b51), S(O)₂NR^(c51)R^(d51), and BR^(h51)R^(i51); wherein        said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and        5-10 membered heteroaryl-C₁₋₃ alkylene, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁵²;    -   each R⁵² is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,        CN, OR^(a52), SR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52),        C(O)OR^(a52), OC(O)R^(b52), OC(O)NR^(c52)R^(d52),        NR^(c52)R^(d52), NR^(c52)C(O)R^(d52), NR^(c52)C(O)OR^(a52),        NR^(c2)C(O)NR^(c52)R^(d52), NR⁵²S(O)R^(b52),        NR^(c52)S(O)₂R^(b52), NR^(c52)S(O)₂NR^(c52)R^(d52), S(O)R^(b52),        S(O)NR^(c52)R^(d52), S(O)₂R^(b52), S(O)₂NR^(c52)R^(d52), and        BR^(h52)R^(i52); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and        4-7 membered heterocycloalkyl, are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        R^(g);    -   each R⁶⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a60),        SR^(a60), C(O)R^(b60),        C(O)NR^(c60)R^(d60)(O)OR^(a60)C(O)R^(b60)C(O)NR^(c60)R^(d60),        NR^(c60)R^(d60), NR^(c60)C(O)R^(b60), NR^(c60)C(O)OR^(a60),        NR^(c60)C(O)NR^(c60)R^(d60), NR^(c60)S(O)R^(d60),        NR^(c60)S(O)₂R^(b60), NR^(c60)S(O)₂NR^(c60)R^(d60), S(O)R^(b60),        S(O)NR^(c60)R^(d60)S(O)₂R^(b60), S(O)₂NR^(c60)R^(d60), and        BR^(h60)R^(i60); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R^(g);    -   each R⁷⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a70),        SR^(a70), C(O)R^(b70), C(O)NR^(c70)R^(d70),        C(O)OR^(a70)C(O)R^(b70)C(O)NR^(c70)R^(d70), NR^(c70)R^(d70),        NR^(c70)C(O)R^(b70), NR^(c70)C(O)OR^(a70),        NR^(c70)C(O)NR^(c70)R^(d70), NR^(c70)S(O)R^(b70),        NR^(c70)S(O)₂R^(b70), NR^(c70)S(O)₂NR^(c70)R^(d70), S(O)R^(b70),        S(O)NR^(c70)R^(d70), S(O)₂R^(b70), S(O)₂NR^(c70)R^(d70), and        BR^(h70)R^(i70); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁷¹;    -   each R⁷¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a71),        SR^(a71), C(O)R^(b71), C(O)NR^(c71)R^(d71), C(O)OR^(a71),        OC(O)R^(b71), OC(O)NR^(c71)R^(d71), NR^(c71)R^(d71), NR^(c71),        C(O)R^(b71), NR^(c71), C(O)OR^(a71),        NR^(c71)C(O)NR^(c71)R^(d71), NR⁷¹S(O)R^(b71),        NR^(c71)S(O)₂R^(b71), NR^(c71)S(O)₂NR^(c71)R^(d71), S(O)R^(b71),        S(O)NR^(c71)R^(d71), S(O)₂R^(b71), S(O)₂NR^(c71)R^(d71), and        BR^(h71)R^(i71); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁷²;    -   each R⁷² is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,        CN, OR^(a72), SR^(a72), C(O)R^(b72), C(O)NR^(c72)R^(d72),        C(O)OR^(a72), OC(O)R^(b72), OC(O)NR^(c72)R^(d72),        NR^(c72)R^(d72), NR^(c72)C(O)R^(b72), NR^(c72)C(O)OR^(a72),        NR^(c72)C(O)NR^(c72)R^(d72), NR^(c72)S(O)R^(b72),        NR^(c72)S(O)₂R^(b72), NR^(c72)S(O)₂NR^(c72)R^(d72), S(O)R^(b72),        S(O)NR^(c72)R^(d72), S(O)₂R^(b72), S(O)₂NR^(c72)R^(d72), and        BR^(h72)R^(i72); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and        4-7 membered heterocycloalkyl, are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        R^(g);    -   each R^(a1), R^(b1), R^(c1), and R^(d1) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and        4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, and 4-7 membered heterocycloalkyl, are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R^(g);    -   or any R^(c1) and R^(b1) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R^(g);    -   each R^(h1) and R^(i1) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h1) and R^(i1) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a2), R^(b2), R^(c2) and R^(d2) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R²⁰;    -   or any R^(c2) and R^(d2) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R²⁰;    -   each R^(e2) is independently selected from H, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl,        carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,        aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆        alkyl)aminosulfonyl;    -   each R^(h2) and R^(i2) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h2) and R^(i2) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a3), R^(b3), R^(c3) and R^(d3) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,        5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10        membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene, and 5-10 membered heteroaryl-C₁₋₃ alkylene; wherein        said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and        5-10 membered heteroaryl-C₁₋₃ alkylene, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R³⁰;    -   or any R^(c3) and R^(d3) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R³⁰;    -   each R^(e3) is independently selected from H, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl,        carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,        aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆        alkyl)aminosulfonyl;    -   each R^(h3) and R^(i3) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h3) and R^(i3) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a5), R^(b5), R^(c5) and R^(d5) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁵⁰;    -   or any R^(c5) and R^(d5) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R⁵;    -   each R^(e5) is independently selected from H, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl,        carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,        aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆        alkyl)aminosulfonyl;    -   each R^(h5) and R^(i5) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h5) and R^(i5) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a6), R^(b6), R^(c6) and R^(d6) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₃₋₁₀ aryl and        5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁶⁰;    -   or any R^(c6) and R^(d6) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R⁶⁰;    -   each R^(e6) is independently selected from H, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl,        carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,        aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆        alkyl)aminosulfonyl;    -   each R^(h6) and R^(i6) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h6) and R^(i6) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a7), R^(b7), R^(c7) and R^(d7) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁷⁰;    -   or any R^(c7) and R^(d7) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R⁷⁰;    -   each R^(e70) is independently selected from H, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl,        carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,        aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆        alkyl)aminosulfonyl;    -   each R^(h7) and R^(i7) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h7) and R^(i7) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a9), R^(b9), R^(c9), and R^(d9) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and        4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, and 4-7 membered heterocycloalkyl, are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R^(g);    -   or any R^(c9) and R^(d9) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R^(g);    -   each R^(h9) and R^(i9) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h9) and R^(i9) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a10), R^(b10), R^(c10) and R^(d10) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R¹¹;    -   or any R^(c10) and R^(d10) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R¹¹;    -   each R^(e10) is independently selected from H, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl,        carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,        aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆        alkyl)aminosulfonyl;    -   each R^(h10) and R^(i10) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h10) and R^(i10) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a11), R^(b11), R^(c11) and R^(d11), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl and 4-7 membered heterocycloalkyl are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R¹²;    -   or any R^(c11) and R^(d11) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R¹²;    -   each R^(h11) and R^(i11) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h11) and R^(i11) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a12), R^(b12), R^(c12) and R^(d12), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆        haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆        alkynyl are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R^(g);    -   each R^(h12) and R^(i12) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h12) and R^(i12) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a20), R^(b20), R^(c20) and R^(d20) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R²¹;    -   or any R^(c20) and R^(d20) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R²¹;    -   each R^(h20) and R^(i20) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h20) and R^(i20) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a21), R^(b21), R^(c21) and R^(d21), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl and 4-7 membered heterocycloalkyl are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R²²;    -   or any R^(c2)1 and R^(d21) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R²²;    -   each R^(h21) and R^(i21) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h21) and R^(i21) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a22), R^(b22), R^(c22) and R^(d22), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆        haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆        alkynyl are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R^(g);    -   each R^(h22) and R^(i22) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h22) and R^(i22) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a30), R^(b30), R^(c30) and R^(d30) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R³¹;    -   or any R^(c30) and R^(d30) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R³¹;    -   each R^(e30) is independently selected from H, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl,        carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,        aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆        alkyl)aminosulfonyl;    -   each R^(h30) and R^(i30) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h30) and R^(i30) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a31), R^(b31), R^(c31) and R^(d31), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl and 4-7 membered heterocycloalkyl are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R³²;    -   or any R^(c31) and R^(d31) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R³²;    -   each R^(h31) and R^(i31) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h31) and R^(i31) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a32), R^(b32), R^(c32) and R^(d32), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆        haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆        alkynyl are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R^(g);    -   each R^(h32) and R^(i32) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h32) and R^(i32) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a50), R^(b50), R^(c50) and R^(d50), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein said C₁₋₆        alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀        cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10        membered heteroaryl, are each optionally substituted with 1, 2,        3, or 4 substituents independently selected from R⁵¹;    -   or any R^(c50) and R^(d50) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R⁵¹;    -   each R^(h50) and R^(i50) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h50) and R^(i50) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a51), R^(b51), R^(c51) and R^(d51), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl and 4-7 membered heterocycloalkyl are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁵²;    -   or any R^(c51) and R^(d51) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R⁵²;    -   each R^(h51) and R^(i51) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h51) and R^(i51) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a52), R^(b52), R^(c52) and R^(d52), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆        haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆        alkynyl are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R^(g);    -   each R^(h52) and R^(i52) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h52) and R^(i32) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a60), R^(b60), R^(c60) and R^(d60), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl;        wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R^(g);    -   or any R^(c60) and R^(d60) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R^(g);    -   each R^(h60) and R^(i60) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h60) and R^(i60) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a70), R^(b70), R and R^(d70) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁷¹; or any R^(c70) and R^(d70) attached to the        same N atom, together with the N atom to which they are        attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁷¹;    -   each R^(h70) and R^(i70) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h70) and R^(i70) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a71), R^(b71), R^(c71) and R^(d71), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl and 4-7 membered heterocycloalkyl are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁷²;    -   or any R^(c71) and R^(d71) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R⁷²;    -   each R^(h71) and R^(i71) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h71) and R^(i71) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a72), R^(b72), R^(c72) and R^(d72), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆        haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆        alkynyl are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R^(g);    -   each R^(h72) and R^(i72) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h72) and R^(i72) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; and    -   each R^(g) is independently selected from D, OH, NO₂, CN, halo,        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆        cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆        haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy,        HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl,        amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆        alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,        C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆        alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino,        C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkylcarbonyloxy,        aminocarbonyloxy, C₁₋₆ alkylaminocarbonyloxy, di(C₁₋₆        alkyl)aminocarbonyloxy, C₁₋₆ alkylsulfonylamino, aminosulfonyl,        C₁₋₆ alkylaminosulfonyl, di(C₁₋₆alkyl)aminosulfonyl,        aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆        alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆        alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In an embodiment of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof,

-   -   represents a single bond or a double bond;    -   X is N or CR⁷;    -   Y is O, NR^(5N), C═O, or C(R⁵)₂;    -   W is C═O, or C(R⁸)₂;    -   Z is O, NR^(9N), C(R⁹)₂, or a bond;    -   R¹ is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a1),        SR^(a1), C(O)R1^(b), C(O)NR^(c1)R^(d1), C(O)OR^(a1),        OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1),        NR^(c1)C(O)R^(d1), NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1),        NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)₂R^(b1), and        S(O)₂NR^(c1)R^(d1);    -   R² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a2), SR^(a2),        C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),        OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(d2),        NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2),        NR^(c2)S(O)₂R^(b2), NR²S(O)₂NR^(c2)R^(d2), S(O)₂R^(b2), and        S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R²⁰;    -   Cy is selected from C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;        wherein the 4-10 membered heterocycloalkyl and 5-10 membered        heteroaryl each has at least one ring-forming carbon atom and 1,        2, 3, or 4 ring-forming heteroatoms independently selected from        N, O, and S; wherein the N and S are optionally oxidized;        wherein a ring-forming carbon atom of 5-10 membered heteroaryl        and 4-10 membered heterocycloalkyl is optionally substituted by        oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl are each optionally substituted with 1, 2, 3 or 4        substituents independently selected from R₁₀;    -   when R³N        CR⁴ is a single bond, then R⁴ is selected from ═O and ═S; and    -   R³ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10 membered        heteroaryl-C₁₋₃ alkylene; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃        alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀        aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene        are each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R³⁰;    -   when R³N        CR⁴ is a double bond, then R³ is absent; and    -   R⁴ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a3), SR^(a3),        C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),        OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),        NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),        NR^(c3)S(O)₂R^(b3), NR^(c1)S(O)₂NR^(c3)R^(d3), S(O)₂R^(b3), and        S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R³⁰;    -   R^(5N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10 membered        heteroaryl-C₁₋₃ alkylene; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃        alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀        aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene        are each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁵⁰;    -   each R⁵ and R⁸ are independently selected from H, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a5),        SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),        OC(O)R^(b5), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),        NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5),        NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)₂R^(b5), and        S(O)₂NR^(c5)R^(d5);    -   ring A is selected from C₃₋₁₀ cycloalkyl and 4-14 membered        heterocycloalkyl; wherein the 4-14 membered heterocycloalkyl has        at least one ring-forming carbon atom and 1, 2, 3, or 4        ring-forming heteroatoms independently selected from N, O, and        S; wherein the N and S are optionally oxidized; wherein a        ring-forming carbon atom of 4-14 membered heterocycloalkyl is        optionally substituted by oxo to form a carbonyl group;    -   n is 0, 1, or 2;    -   each R⁶ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a6), SR^(a6),        C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),        OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),        NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6),        NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)₂R^(b6), and        S(O)₂NR^(c6)R^(d6);    -   R⁷ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a7), SR^(a7),        C(O)R^(b7), C(O)NR^(c7)R^(d7), (O)OR^(a7), OC(O)R^(b7),        OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR^(c7)C(O)R^(b7),        NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7) NR⁷S(O)₂R^(b7),        NR⁷S(O)₂NR^(c7)R^(d7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7);    -   R^(9N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, and 4-7 membered heterocycloalkyl;    -   each R⁹ is independently selected from selected from H, D, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆        cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, halo, CN, OR^(a9), SR^(a9), C(O)R^(b9),        C(O)NR^(c9)R^(d9), (O)OR^(a9), C(O)R^(b9), OC(O)NR^(c9)R^(d9),        NR^(c9)R^(d9), NR⁹C(O)R^(b9), NR⁹C(O)OR^(a9),        NR⁹C(O)NR^(c9)R^(d9), NR⁹S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9),        S(O)₂R^(b9), and S(O)₂NR^(c9)R^(d9);    -   each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a10),        SR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10),        C(O)OR^(a10)(O)R^(b10), OC(O)NR^(c10)R^(d10), NR^(c10)R^(d10),        NR^(c10), C(O)R^(b10), NR^(c10)C(O)OR^(a10),        NR^(c10)C(O)NR^(c10)R^(d10) NR^(c1)S(O)₂R^(b10),        NR^(c10)S(O)₂NR^(c10)R^(d10), S(O)R^(b10), and        S(O)₂NR^(c10)R^(d10);    -   each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a20),        SR^(a20), C(O)R^(b20), C(O)NR^(c20)R^(d20), C(O)OR^(a20),        OC(O)R^(b20), OC(O)NR^(c20)R^(d20), NR^(c20)R^(d20),        NR^(c20)C(O)R^(b20), NR^(c20)C(O)OR^(a20),        NR^(c20)C(O)NR^(c20)R^(d20), NR^(c20)S(O)₂R^(b20),        NR^(c20)S(O)₂NR^(c20)R^(d20), S(O)₂R^(b20), and        S(O)₂NR^(c20)R^(d20); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃        alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀        aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene        are each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R²¹;    -   each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a21),        SR^(a21), C(O)R^(b21), C(O)NR^(c21)R^(d21), C(O)OR^(a21),        OC(O)R^(b21), OC(O)NR^(c21)R^(d21), NR^(a21)R^(b21),        NR^(c21)C(O)R^(b21), NR^(c21)C(O)OR^(a21),        NR^(c21)C(O)NR^(c21)R^(d21), NR^(c21)S(O)₂R^(b21),        NR^(c21)S(O)₂NR^(c21)R^(d21), S(O)₂R^(b21), and        S(O)₂NR^(c21)R^(d21);    -   each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a30),        SR^(a30), C(O)R^(b30), C(O)NR^(c30)R^(d30), C(O)OR^(a3),        OC(O)R^(b30), OC(O)NR^(c30)R^(d30), NR^(c30)R^(d30),        NR^(c30)C(O)R^(b30), NR^(c30)C(O)OR^(a30),        NR^(c30)C(O)NR^(c30)R^(d30), NR^(c30)S(O)₂R^(b30),        NR^(c30)S(O)₂NR^(c30)R^(d30) S(O)₂R^(b30), and        S(O)₂NR^(c30)R^(d30); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃        alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀        aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene        are each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R³¹;    -   each R³¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a31),        SR^(a31), C(O)R^(b31), C(O)NR^(c31)R^(d31), C(O)OR^(a31),        OC(O)R^(b31), OC(O)NR^(c31)R^(d31), NR^(c31)R^(d31),        NR^(c31)C(O)R^(b31), NR^(c31)C(O)OR^(a31),        NR^(c31)C(O)NR^(c1)R^(d31), NR^(c31)S(O)₂R^(b31),        NR^(c31)S(O)₂NR^(c31)R^(d31), S(O)₂R^(b31), and        S(O)₂NR^(c31)R^(d31);    -   each R⁵⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a50),        SR^(a50), C(O)R^(b50), C(O)NR^(c50)R^(d50), C(O)OR^(a50),        OC(O)R^(b50), OC(O)NR^(c50)R^(d50), NR^(c50)R^(d50),        NR^(c50)C(O)R^(b50), NR^(c50)C(O)OR^(a50),        NR^(c50)C(O)NR^(c50)R^(d50), NR^(c50)S(O)₂R^(b50),        NR^(c50)S(O)₂NR^(c50)R^(d50), S(O)₂R^(b50), and        S(O)₂NR^(c50)R^(d50);    -   each R^(a1), R^(b1), R^(c1), and R^(d1) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and        4-7 membered heterocycloalkyl;    -   or any R^(c1) and R^(d1) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group;    -   each R^(a2), R^(b2), R^(c2) and R^(d2) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R²⁰;    -   or any R^(c2) and R^(d2) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R²⁰;    -   each R^(a3), R^(b3), R^(c3) and R^(d3) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,        5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10        membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene, and 5-10 membered heteroaryl-C₁₋₃ alkylene; wherein        said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and        5-10 membered heteroaryl-C₁₋₃ alkylene, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R³⁰;    -   or any R^(c3) and R^(d3) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R³⁰;    -   each R^(a5), R^(b5), R^(c5) and R^(d5) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl;    -   or any R^(c5) and R^(d5) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group;    -   each R^(a6), R^(b6), R^(c6) and R^(d6) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl;    -   or any R^(c6) and R^(d6) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group;    -   each R^(a7), R^(b7), R^(c7) and R^(d7) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl;    -   or any R^(c7) and R^(d7) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group;    -   each R^(a9), R^(b9), R^(c9), and R^(d9) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and        4-7 membered heterocycloalkyl;    -   or any R^(c9) and R^(d9) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group;    -   each R^(a10), R^(b10), R^(c10) and R^(d10) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl;    -   or any R^(c10) and R^(d10) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group;    -   each R^(a20), R^(b20), R^(c20) and R^(d20) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R²¹;    -   or any R^(c20) and R^(d20) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R²¹;    -   each R^(a21), R^(b21), R^(c21) and R^(d21), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl;    -   or any R^(c21) and R^(d21) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group;    -   each R^(a30), R^(b30), R^(c30) and R^(d30) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R³¹;    -   or any R^(c30) and R^(d30) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R³¹;    -   each R^(a31), R^(b31), R^(c31) and R^(d31), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl;    -   or any R^(c31) and R^(d31) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group; and    -   each R^(a50), R^(b50), R^(c50) and R^(d50), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, and 5-10 membered heteroaryl;    -   or any R^(c10) and R^(d50) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group.

In yet another embodiment, the compound of Formula I is a compound ofFormula II:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   Y is NR^(5N), or C═O;    -   W is C═O, or C(R⁸)₂;    -   Z is O, NR^(9N), or a bond;    -   R¹ is selected from H, D, C₁₋₆ alkyl, halo, and CN;    -   R² is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, CN,        OR^(a2), and NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, is        optionally substituted with 1, 2, or 3 substituents        independently selected from R²⁰;    -   Cy is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl;        wherein the 5-10 membered heteroaryl each has at least one        ring-forming carbon atom and 1, 2, 3, or 4 ring-forming        heteroatoms independently selected from N, O, and S; wherein the        N and S are optionally oxidized; wherein a ring-forming carbon        atom of 5-10 membered heteroaryl is optionally substituted by        oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryl and        5-10 membered heteroaryl are each optionally substituted with 1,        2, or 3 substituents independently selected from R¹⁰;    -   R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀        cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10        membered heteroaryl, halo, D, CN, OR^(a3), and NR^(c3)R^(d3);        wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl, are        each optionally substituted with 1, 2, or 3 substituents        independently selected from R³⁰;    -   R^(5N) is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;        wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or        3 substituents independently selected from R⁵⁰;    -   R⁸ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, CN,        OR^(a5), and NR^(c5)R^(d5);    -   ring A is selected from C₃₋₁₀ cycloalkyl and 4-14 membered        heterocycloalkyl; wherein the 4-14 membered heterocycloalkyl has        at least one ring-forming carbon atom and 1, 2, 3, or 4        ring-forming heteroatoms independently selected from N, O, and        S; wherein the N and S are optionally oxidized; wherein a        ring-forming carbon atom of 4-14 membered heterocycloalkyl is        optionally substituted by oxo to form a carbonyl group;    -   n is 0, 1, or 2;    -   each R⁶ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, halo, D, CN, OR^(a6), C(O)R^(b6), C(O)NR^(c6)R^(d6),        C(O)OR^(a6), NR^(c6)R^(d6), and NR^(c6)C(O)R^(b6);    -   R⁷ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, CN,        OR^(a7), and NR^(c7)R^(d7);    -   R^(9N) is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;    -   each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, halo, D, CN, OR^(a10), and NR^(c10)R^(d10);    -   each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN, OR^(a20), and        NR^(c20)R^(d20); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, or 3        substituents independently selected from R²¹;    -   each R²¹ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl halo, D, CN, OR^(a21) and NR^(c21)R^(c21);    -   each R³⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN, OR^(a30) and,        NR^(c30)R^(d30); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, or 3        substituents independently selected from R³¹;    -   each R³¹ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, halo, D, CN, OR^(a31), and NR^(c31)R^(d31);    -   each R⁵⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, halo, D, CN, OR^(a50), C(O)R^(b50),        C(O)NR^(c50)R^(d50), C(O)OR^(a50), NR^(c50)R^(d50), and        NR^(c50)C(O)R^(b50);    -   each R^(a2), R^(c2) and R^(d2) is independently selected from H,        C₁₋₆ alkyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, is        optionally substituted with 1, 2, or 3 substituents        independently selected from R²⁰;    -   each R^(a3), R^(c3) and R^(d3) is independently selected from H,        C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl;        wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl, are        each optionally substituted with 1, 2, or 3 substituents        independently selected from R³⁰;    -   or any R^(c3) and R^(d3) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, or        6-membered heterocycloalkyl group optionally substituted with 1,        2, or 3 substituents independently selected from R³⁰;    -   each R^(a5), R^(c5) and R^(d5) is independently selected from H,        C₁₋₆ alkyl, and C₁₋₆ haloalkyl;    -   each R^(a6), R^(b6), R^(c6) and R^(d6) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆        haloalkyl;    -   each R^(a7), R^(b7), R^(c7) and R^(d7) is independently selected        from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;    -   each R^(a10), R^(c10) and R^(d10) is independently selected from        H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;    -   each R^(a20), R^(c20) and R^(d20) is independently selected from        H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀        cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10        membered heteroaryl; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, or 3        substituents independently selected from R²¹;    -   or any R^(c20) and R^(d20) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, or        6-membered heterocycloalkyl group optionally substituted with 1,        2, or 3 substituents independently selected from R²¹;    -   each R^(a21), R^(c21) and R^(d21), is independently selected        from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;    -   each R^(a30), R^(c30) and R^(d30) is independently selected from        H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;        wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, are        each optionally substituted with 1, 2, or 3 substituents        independently selected from R³¹;    -   or any R^(c30) and R^(d30) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, or        6-membered heterocycloalkyl group optionally substituted with 1,        2, or 3 substituents independently selected from R³¹;    -   each R^(a31), R^(c31) and R^(d31), is independently selected        from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and    -   each R^(a50), R^(b50), R^(c50) and R^(d50), is independently        selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In an embodiment of a compound of Formula II, or a pharmaceuticallyacceptable salt thereof,

-   -   Y is NR^(5N), or C═O;    -   W is C═O, or C(R⁸)₂;    -   Z is O, NR^(9N), or a bond;    -   R¹ is selected from H, D, C₁₋₃ alkyl, and halo;    -   R² is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, and        CN; wherein said C₁₋₆ alkyl, is optionally substituted with 1 or        2 substituents independently selected from R²⁰;    -   Cy is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl;        wherein the 5-10 membered heteroaryl each has at least one        ring-forming carbon atom and 1, 2, or 3 ring-forming heteroatoms        independently selected from N and O; wherein a ring-forming        carbon atom of 5-10 membered heteroaryl is optionally        substituted by oxo to form a carbonyl group; and wherein the        C₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally        substituted with 1, 2, or 3 substituents independently selected        from R¹⁰;    -   R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆        cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered        heteroaryl, halo, D, CN, OR^(a3), and NR^(c3)R^(d3); wherein        said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,        phenyl, and 5-6 membered heteroaryl, are each optionally        substituted with 1, 2, or 3 substituents independently selected        from R³⁰;    -   R^(5N) is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;        wherein said C₁₋₆ alkyl is optionally substituted with 1, 2, or        3 substituents independently selected from R⁵⁰;    -   R⁸ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, and        CN;    -   ring A is selected from C₃₋₆ cycloalkyl and 4-6 membered        heterocycloalkyl; wherein the 4-14 membered heterocycloalkyl has        at least one ring-forming carbon atom and 1 or 2 ring-forming        heteroatoms independently selected from N and O; wherein a        ring-forming carbon atom of 4-6 membered heterocycloalkyl is        optionally substituted by oxo to form a carbonyl group;    -   n is 0, 1, or 2;    -   each R⁶ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, halo, D, CN, OR^(a), C(O)R^(b), and NR^(c6)R^(d6);    -   R⁷ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, and        CN;    -   R^(9N) is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;    -   each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, halo, D, CN, OR^(a21), and NR^(c10)R^(d10);    -   each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN,        OR^(a20), and NR^(c20)R^(d20); wherein said C₁₋₆ alkyl, phenyl,        and 5-6 membered heteroaryl, are each optionally substituted        with 1 or 2 substituents independently selected from R²¹;    -   each R²¹ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl halo, D, CN, OR^(a21) and NR^(c21)R^(d21);    -   each R³⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,        phenyl, 5-6 membered heteroaryl, halo, D, CN, OR^(a30) and,        NR^(c30)R^(d30); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 4-6        membered heterocycloalkyl, phenyl, and 5-6 membered heteroaryl,        are each optionally substituted with 1 or 2 substituents        independently selected from R³¹;    -   each R³¹ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, halo, D, CN, OR^(a31), and NR^(c31)R^(d31);    -   each R⁵⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆        haloalkyl, halo, D, CN, OR^(a50), C(O)NR^(c50)R^(d50),        NR^(c50)R^(d50), and NR^(c50), C(O)R^(b50);    -   each R^(a3), R^(c3) and R^(d3) is independently selected from H,        C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl;        wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl, are        each optionally substituted with 1, 2, or 3 substituents        independently selected from R³⁰;    -   or any R^(c3) and R^(d3) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, or        6-membered heterocycloalkyl group optionally substituted with 1,        2, or 3 substituents independently selected from R³⁰;    -   each R^(a6), R^(b6), R^(c6) and R^(d6) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆        haloalkyl;    -   each R^(a10), R^(c10) and R^(d10) is independently selected from        H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;    -   each R^(a20), R^(c20) and R^(d20) is independently selected from        H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl and 5-6 membered        heteroaryl; wherein said C₁₋₆ alkyl, phenyl and 5-6 membered        heteroaryl, are each optionally substituted with 1 or 2        substituents independently selected from R²¹;    -   each R^(a21), R^(c21) and R^(d21), is independently selected        from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl;    -   each R^(a30), R^(c30) and R^(d30) is independently selected from        H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered        heterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein        said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,        phenyl and 5-6 membered heteroaryl, are each optionally        substituted with 1 or 2 substituents independently selected from        R³¹;    -   or any R^(c30) and R^(d30) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, or        6-membered heterocycloalkyl group optionally substituted with 1        or 2 substituents independently selected from R³¹;    -   each R^(a31), R^(c31) and R^(d31), is independently selected        from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; and    -   each R^(a50), R^(c50) and R^(d50), is independently selected        from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.

In another embodiment of Formula II,

-   -   Y is NH, N(C₁₋₆ alkyl), or C═O; wherein said alkyl is optionally        substituted with 1 or 2 substituents independently selected from        halo, OH, C(O)NH₂, and CN;    -   W is C═O, or C(R⁸)₂;    -   Z is O, NR^(9N), or a bond;    -   R¹ is H or halo;    -   R² is H, halo, or C₁₋₆ alkyl; wherein said C₁₋₆ alkyl, is        optionally substituted with 1 or 2 substituents independently        selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, phenyl, 5-6 membered        heteroaryl, halo, D, CN, OH, and O(C₁₋₆ alkyl); wherein phenyl        is optionally substituted with 1 or 2 substituents independently        selected from halo and CN;    -   Cy is C₆₋₁₀ aryl or 5-10 membered heteroaryl; both of which are        optionally substituted with 1, 2, 3 or 4 substituents        independently selected from C₁₋₆ alkyl, halo, OH, and O(C₁₋₆        alkyl);    -   R⁴ is selected from H, C₁₋₆ alkyl, O(C₁₋₆ alkyl), C₃₋₆        cycloalkyl, and 4-6 membered heterocycloalkyl, wherein said        alkyl, cycloalkyl, and heterocycloalkyl are each optionally        substituted one or two times with 4-10 membered heterocycloalkyl        which is optionally substituted with C₁₋₆ alkyl, NH₂, or N(C₁₋₆        alkyl)₂;    -   each R⁵ and R⁶ are independently selected from H, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, halo, D, and CN;    -   ring A is 4-7 membered heterocycloalkyl;    -   n is 0, 1, or 2;    -   each R⁶ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, OH, O(C₁₋₆ alkyl),        NH₂, N(C₁₋₆ alkyl)₂, C(O)H, C(O)C₁₋₆ alkyl, and C(O)C₂₋₆        alkenyl;    -   R⁷ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, CN,        OH, and O(C₁₋₆ alkyl); and    -   R^(9N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, and C₁₋₆ haloalkyl.

In another aspect, provided herein is a compound of Formula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   represents a single bond or a double bond;    -   X is N or CR⁷;    -   Y is O, NR^(5N), C═O, or C(R⁵)₂;    -   W is C═O, or C(R⁸)₂;    -   Z is O, NR^(9N), O(R⁹)₂, or a bond;    -   R¹ and R² are each independently selected from H, D, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,        phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl,        halo, CN, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), (O)OR^(a),        OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),        NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)R^(b),        NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),        S(O)NR^(c)R^(d), S(O)₂R^(b), S(O)₂NR^(c)R^(d), and BR^(h)R^(i);        wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆        cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered        heterocycloalkyl, are each optionally substituted with 1, 2, 3,        or 4 substituents independently selected from R^(g);    -   Cy is selected from C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;        wherein the 4-10 membered heterocycloalkyl and 5-10 membered        heteroaryl each has at least one ring-forming carbon atom and 1,        2, 3, or 4 ring-forming heteroatoms independently selected from        N, O, and S; wherein the N and S are optionally oxidized;        wherein a ring-forming carbon atom of 5-10 membered heteroaryl        and 4-10 membered heterocycloalkyl is optionally substituted by        oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl are each optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹⁰;    -   when R³N        CR⁴ is a single bond, then R⁴ is selected from ═O and ═S;    -   R³ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10 membered        heteroaryl-C₁₋₃ alkylene; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃        alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀        aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene        are each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R³⁰;    -   when R³N        CR⁴ is a double bond, then R³ is absent;    -   R⁴ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a3), SR^(a3),        C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3),        OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),        NR^(c3)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3), C(═NR^(e3))R^(b3),        C(═NOR^(a3))R^(b3), C(═NR^(e3))NR^(c3)R^(d3),        NR^(c3)C(═NR^(e3))NR^(c3)R^(d3), NR^(c3)C(═NR^(e3))R^(b3),        NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR³³S(O)₂NR^(c3)R^(d3),        S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), S(O)₂NR^(c3)R^(d3),        and BR^(h3)R^(i3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R³⁰;    -   R^(5N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and 5-10 membered        heteroaryl-C₁₋₃ alkylene; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃        alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀        aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene        are each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁵⁰;    -   each R⁵ and R⁸ are independently selected from H, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a5),        SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), (O)OR^(a5), OC(O)R^(b5),        OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5),        NR^(c5)C(O)OR^(a5), NR^(c5)C(O)NR^(c5)R^(d5), C(═NR^(e5))R^(b5),        C(═NOR^(a5))R^(5b), C(═NR^(e5))NR^(c5)R^(d5),        NR^(c5)C(═NR^(e5))NR^(c5)R^(d5), NR^(c5)C(═NR^(e4))R^(b5),        NR^(c5)S(O)R^(b5), NR^(c5)S(O)₂R^(b5),        NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5), S(O)NR^(c5)R^(d5),        S(O)₂R^(b5), S(O)₂NR^(c5)R^(d5), and BR^(h5)R^(i5); wherein said        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and        5-10 membered heteroaryl-C₁₋₃ alkylene are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁵⁰;    -   ring A is C₃₋₁₄ cycloalkyl or 4-14 membered heterocycloalkyl;        wherein the 4-14 membered heterocycloalkyl has at least one        ring-forming carbon atom and 1, 2, 3, or 4 ring-forming        heteroatoms independently selected from N, O, and S; wherein the        N and S are optionally oxidized; wherein a ring-forming carbon        atom of 4-14 membered heterocycloalkyl is optionally substituted        by oxo to form a carbonyl group;    -   n is 0, 1, 2, 3, or 4;    -   each R⁶ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a6), SR^(a6),        C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),        OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),        NR^(c6)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6), C(═NR^(e6))R^(b6),        C(═NOR^(a6))R^(b6), C(═NR^(e6))NR^(c6)R^(d6),        NR^(c6)C(═NR^(e6))NR^(c6)R^(d6), NRO6C(═NR^(e6))R^(b6),        NR^(c6)S(O)R^(b6), NR⁶S(O)₂R^(b6), NR⁶S(O)₂NR^(c6)R^(d6),        S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), S(O)₂NR^(c6)R^(d6),        and BR^(h6)R^(i6); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁶⁰;    -   R⁷ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a7), SR^(a7),        C(O)R^(b7), C(O)NR^(c7)R^(d7), (O)OR^(a7), C(O)R^(b7),        OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7), NR⁷C(O)R^(b7),        NR⁷C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7), C(═NR^(e7))R^(b7),        C(═NOR^(a7))R^(b7), C(═NR^(e7))NR^(c7)R^(d7),        NR^(c7)C(═NR^(e7))NR^(c7)R^(d7), NR^(c7)C(═NR^(e7))R^(b7),        NR^(c7)S(O)R^(b7), NR⁷S(O)₂R^(b7), NR⁷S(O)₂NR^(c7)R^(d7),        S(O)R^(b7), S(O)NR^(c7)R^(d7), S(O)₂R^(b7), S(O)₂NR^(c7)R^(d7),        and BR^(h7)R^(i7); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁷⁰;    -   R^(9N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, and 4-7 membered heterocycloalkyl; wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6        membered heteroaryl, and 4-7 membered heterocycloalkyl, are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R^(g);    -   each R⁹ is independently selected from selected from H, D, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆        cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, halo, CN, OR^(a9), SR^(a9), C(O)R^(b9),        C(O)NR^(c9)R^(d9), (O)OR^(a9), OC(O)R^(b9), OC(O)NR^(c9)R^(d9),        NR^(c9)R^(d9), NR^(c9)C(O)R^(b9), NR^(c9)C(O)OR^(a9),        NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9), NR^(c9)S(O)₂R^(b9),        NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9), S(O)NR^(c9)R^(d9),        S(O)₂R^(b9), S(O)₂NR^(c9)R^(d9), and BR^(h9)R^(i9); wherein said        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl,        5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, are        each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R^(g);    -   each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a10),        SR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10), C(O)OR^(a10),        CO(O)R^(b10), OC(O)NR^(c10)R^(d10), NR^(c10)R^(d10), NR^(c10),        C(O)R^(b10), NR^(c10)C(O)OR^(a10), NR^(c10)C(O)NR^(c10)R^(d10),        C(═NR^(e10))R^(b10), C(═NOR^(a10))R^(b10),        C(═NR^(e10))NR^(c10)R^(d10),        NR^(c10)C(═NR^(e10))NR^(c10)R^(d10),        NR^(c10)C(═NR^(e10))R^(b10), NR^(c10)S(O)R^(b10),        NR^(c10)S(O)₂R^(b10), NR^(c10)S(O)₂NR^(c10)R^(d10), S(O)R^(b10),        S(O)NR^(c10)R^(d10), S(O)₂R^(b10), S(O)₂NR^(c10)R^(d10), and        BR^(h10)R^(i10); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R¹¹;    -   each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a11),        SR^(a11), C(O)R^(b11), C(O)NR^(c11)R^(d11), C(O)OR^(a11),        OC(O)R^(b11), OC(O)NR^(c11)R^(d11), NR^(c11)R^(d11),        NR^(c11)C(O)R^(b11), NR^(c11)C(O)OR^(a11),        NR^(c11)C(O)NR^(c11)R^(d11), NR^(c11)S(O)R^(b11),        NR^(c11)S(O)₂R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11), S(O)R^(b11),        S(O)NR^(c11)R^(d11), S(O)₂R^(b11), S(O)₂NR^(c11)R^(d11), and        BR^(h11)R^(i11); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R¹²;    -   each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,        CN, OR^(a12), SR^(a12), C(O)R^(b12), C(O)NR^(c12)R^(d12),        C(O)OR^(a12), OC(O)R^(b12), OC(O)NR^(c12)R^(d12),        NR^(c12)R^(d12), NR^(c12)C(O)R^(b12), NR^(c12)C(O)OR^(a12),        NR^(c12)C(O)NR^(c12)R^(d12), NR^(c12)S(O)R^(b12),        NR^(c12)S(O)₂R^(b12), NR^(c12)S(O)₂NR^(c12)R^(d12), S(O)R^(b12),        S(O)NR^(c12)R^(d12), S(O)₂R^(b12), S(O)₂NR^(c12)R^(d12), and        BR^(h12)R^(i12); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and        4-7 membered heterocycloalkyl, are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        R^(g);    -   each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a30),        SR^(a30), C(O)R^(b30), C(O)NR^(c30)R^(d30),        C(O)OR^(a30)C(O)R^(b30)C(O)NR^(c30)R^(d3), NR^(c3)R^(d3),        NR^(c30)C(O)R^(b30), NR^(c30)C(O)OR^(a30),        NR^(c30)C(O)NR^(c30)R^(d30), C(═NR^(e30))R^(b30),        C(═NOR^(a30))R^(b30), C(═NR^(e30))NR^(c30)R^(d30),        NR^(c30)C(═NR^(e30))NR^(c30)R^(d30),        NR^(c30)C(═NR^(e30))R^(b30), NR^(c30)S(O)R^(b30),        NR^(c30)S(O)₂R^(b30), NR³⁰S(O)₂NR^(c30)R^(d30), S(O)R^(b30),        S(O)NR^(c30)R^(d30), S(O)₂R^(b30), S(O)₂NR^(c30)R^(d30), and        BR^(h30)R^(i30); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R³¹;    -   each R³¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a31),        SR^(a31), C(O)R^(b31), C(O)NR^(c31)R^(d31), C(O)OR^(a31),        OC(O)R^(b31), OC(O)NR^(c31)R^(d31), NR^(c31)R^(d31),        NR^(c31)C(O)R^(b31), NR^(c31)C(O)OR^(a31),        NR^(b31)C(O)NR^(c1)R^(d31), NR^(c1)S(O)R^(b31),        NR^(c31)S(O)₂R^(b31), NR^(c31)S(O)₂NR^(c31)R^(d31), S(O)R^(b31),        S(O)NR^(c31)R^(d31), S(O)₂R^(b31), S(O)₂NR^(c31)R^(d31), and        BR^(h31)R^(i31); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R³²;    -   each R³² is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,        CN, OR^(a32), SR^(a32), C(O)R^(b32),        C(O)NR^(c32)R^(d32)(O)OR^(a32), OC(O)R^(b32),        OC(O)NR^(c32)R^(d32), NR^(c32)R^(d32), NR^(c32)C(O)R^(b32),        NR^(c32)C(O)OR^(a32), NR^(c32)C(O)NR^(c32)R^(d32),        NR^(c32)S(O)R^(b32), NR^(c32)S(O)₂R^(b32),        NR^(c32)S(O)₂NR^(c32)R^(d32), S(O)R^(b32), S(O)NR^(c32)R^(d32),        S(O)₂R^(b32), S(O)₂NR^(c32)R^(d32), and BR^(h32)R^(i32); wherein        said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,        phenyl, 5-6 membered heteroaryl and 4-7 membered        heterocycloalkyl, are each optionally substituted with 1, 2, 3,        or 4 substituents independently selected from R^(g);    -   each R⁵⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a50),        SR^(a50), C(O)R^(b50), C(O)NR^(c50)R^(d50) (O)OR^(a50),        OC(O)R^(b50), OC(O)NR^(c5)R^(d5), NR^(c5)R^(d5),        NR^(c50)C(O)R^(b50), NR^(c50)C(O)OR^(a50),        NR^(c5)C(O)NR^(c50)R^(d50), NR^(c50)S(O)R^(b50),        NR^(c50)S(O)₂R^(b50), NR^(c50)S(O)₂NR^(c50)R^(d50), S(O)R^(b50),        S(O)NR^(c5)R^(d50), S(O)₂R^(b50), S(O)₂NR^(c50)R^(d50), and        BR^(h50)R^(i50); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁵¹;    -   each R⁵¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a51),        SR^(a51), C(O)R^(b51), C(O)NR^(c51)R^(d51), C(O)OR^(a510),        OC(O)R^(b51), OC(O)NR^(c51)R^(d51), NR^(c51)R^(d51),        NR^(c51)C(O)R^(b51), NR^(c51)C(O)OR^(a51),        NR⁵¹C(O)NR^(c51)R^(d51), NR^(c51)S(O)R^(b51), NR⁵¹S(O)₂R^(b51),        NR^(c51)S(O)₂NR^(c51)R^(d51), S(O)R^(b51), S(O)NR^(c51)R^(d51),        S(O)₂R^(b51), S(O)₂NR^(c51)R^(d51), and BR^(h51)R^(i51); wherein        said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and        5-10 membered heteroaryl-C₁₋₃ alkylene, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁵²;    -   each R⁵² is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,        CN, OR^(a52), SR^(a52), C(O)R^(b52), C(O)NR^(c52)R^(d52),        (O)OR^(a52), C(O)R^(b52), OC(O)NR^(c52)R^(d52), NR^(c52)R^(d52),        NR^(c52)C(O)R^(b52), NR^(c52)C(O)OR^(a52),        NR^(c52)C(O)NR^(c52)R^(d52), NR^(c52)S(O)R^(b52),        NR^(c52)S(O)₂R^(b52), NR^(c52)S(O)₂NR^(c52)R^(d52), S(O)R^(b52),        S(O)NR^(c52)R^(d52), S(O)₂R^(b52), S(O)₂NR^(c52)R^(d52), and        BR^(h52)R^(i52); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and        4-7 membered heterocycloalkyl, are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        R^(g);    -   each R⁶⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a60),        SR^(a60), C(O)R^(b60), C(O)NR^(c60)R^(d60), (O)OR^(a60),        OC(O)R^(b60), OC(O)NR^(c60)R^(d60), NR^(c60)R^(d60),        NR^(c60)C(O)R^(b60), NR^(c60)C(O)OR^(a60),        NR^(c60)C(O)NR^(c60)R^(d60), NR⁶⁰S(O)R^(b60),        NR^(c60)S(O)₂R^(b60), NR^(c60)S(O)₂NR^(c60)R^(d60), S(O)R^(b60),        S(O)NR^(c60)R^(d60), S(O)₂R^(b60), S(O)₂NR^(c60)R^(d60), and        BR^(h60)R^(i60); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R^(g);    -   each R⁷⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, NO₂, OR^(a70),        SR^(a70), C(O)R^(b70), C(O)NR^(c70)R^(d70),        C(O)OR^(a70)C(O)R^(b70)C(O)NR^(c70)R^(d70), NR^(c70)R^(d70),        NR^(c70)C(O)R^(b70), NR^(c70)C(O)OR^(a70),        NR^(c7)C(O)NR^(c70)R^(d70), NR^(c70)S(O)R^(b70),        NR⁷⁰S(O)₂R^(b70), NR^(c70)S(O)₂NR^(c70)R^(d70), S(O)R^(b70),        S(O)NR^(c70)R^(d70), S(O)₂R^(b70), S(O)₂NR^(c70)R^(d70), and        BR^(h70)R^(i70); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁷¹;    -   each R⁷¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a71),        SR^(a71), C(O)R^(b71), C(O)NR^(c71)R^(d71), C(O)OR^(a71),        OC(O)R^(b71), OC(O)NR^(c71)R^(d71), NR^(c71)R^(d71),        NR^(c71)C(O)R^(b71), NR^(c71)C(O)OR^(a71),        NR^(c71)C(O)NR^(c71)R^(d71), NR⁷¹S(O)R^(b71), NR⁷¹S(O)₂R^(b71),        NR^(c71)S(O)₂NR^(c71)R^(d71), S(O)R^(b71), S(O)NR^(c71)R^(d71),        S(O)₂R^(b71), S(O)₂NR^(c71)R^(d71), and BR^(h71)R^(i71); wherein        said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and        5-10 membered heteroaryl-C₁₋₃ alkylene are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁷²;    -   each R⁷² is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,        CN, OR^(a72), SR^(a72), C(O)R^(b72), C(O)NR^(c72)R^(d72),        C(O)OR^(a72), OC(O)R^(b72), OC(O)NR^(c72)R^(d72),        NR^(c72)R^(d72), NR^(c72)C(O)R^(b72), NR^(c72)C(O)OR^(a72),        NR^(c72)C(O)NR^(c72)R^(d72), NR^(c72)S(O)R^(b72),        NR^(c72)S(O)₂R^(b72), NR^(c72)S(O)₂NR^(c72)R^(d72), S(O)R^(b72),        S(O)NR^(c72)R^(d72), S(O)₂R^(b72), S(O)₂NR^(c72)R^(d72), and        BR^(h72)R^(i72); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and        4-7 membered heterocycloalkyl, are each optionally substituted        with 1, 2, 3, or 4 substituents independently selected from        R^(g);    -   each R^(a), R^(b), R^(c), and R^(d) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7        membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, and 4-7 membered heterocycloalkyl, are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R^(g);    -   or any R^(c) and R^(d) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R^(g);    -   each R^(h) and R^(i) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h) and R^(i) attached to        the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a3), R^(b3), R^(c3) and R^(d3) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,        5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10        membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene, and 5-10 membered heteroaryl-C₁₋₃ alkylene; wherein        said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and        5-10 membered heteroaryl-C₁₋₃ alkylene, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R³⁰;    -   or any R^(c3) and R^(d3) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R³⁰;    -   each R^(e3) is independently selected from H, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl,        carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,        aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆        alkyl)aminosulfonyl;    -   each R^(h3) and R^(i3) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h3) and R^(i3) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a5), R^(5b), R^(c5) and R^(d5) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁵⁰;    -   or any R^(c5) and R^(d5) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R⁵⁰;    -   each R^(e5) is independently selected from H, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl,        carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,        aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆        alkyl)aminosulfonyl;    -   each R^(h5) and R^(i5) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h5) and R^(i5) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a6), R^(b6), R^(c6) and R^(d6) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁶⁰;    -   or any R^(c6) and R^(d6) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R⁶⁰;    -   each R^(e6) is independently selected from H, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl,        carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,        aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆        alkyl)aminosulfonyl;    -   each R^(h6) and R^(i6) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h6) and R^(i6) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a7), R^(b7), R^(c7) and R^(d7) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁷⁰;    -   or any R^(c7) and R^(d7) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R⁷⁰;    -   each R^(e70) is independently selected from H, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl,        carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,        aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆        alkyl)aminosulfonyl;    -   each R^(h7) and R^(i7) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h7) and R^(i7) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a9), R^(b9), R^(c9), and R^(d9) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and        4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, and 4-7 membered heterocycloalkyl, are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R^(g);    -   or any R^(c9) and R^(d9) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R^(g);    -   each R^(h9) and R^(i9) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h9) and R^(i9) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a10), R^(b10), R^(c10) and R^(d10) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R¹¹; or any R^(c10) and        R^(d10) attached to the same N atom, together with the N atom to        which they are attached, form a 4-, 5-, 6- or 7-membered        heterocycloalkyl group optionally substituted with 1, 2, 3, or 4        substituents independently selected from R¹¹;    -   each R^(e10) is independently selected from H, CN, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl,        carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,        aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆        alkyl)aminosulfonyl;    -   each R^(h10) and R^(i10) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h10) and R^(i10) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a11), R^(b11), R^(c11) and R^(d11), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl and 4-7 membered heterocycloalkyl are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R¹²; or any R^(c11) and R^(d11) attached to the        same N atom, together with the N atom to which they are        attached, form a 4-, 5-, 6- or 7-membered heterocycloalkyl group        optionally substituted with 1, 2 or 3 substituents independently        selected from R¹²;    -   each R^(h11) and R^(i11) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h11) and R^(i11) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a12), R^(b12), R^(c12) and R^(d12), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆        haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆        alkynyl are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R^(g);    -   each R^(h12) and R^(i12) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h12) and R^(i12) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a30), R^(b30), R^(c30) and R^(d30) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R³¹;    -   or any R^(c30) and R^(d30) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R³¹; each        R^(e30) is independently selected from H, CN, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminosulfonyl,        carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,        aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆        alkyl)aminosulfonyl;    -   each R^(h30) and R^(i30) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h30) and R^(i30) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a31), R^(b31), R^(c31) and R^(d31), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl and 4-7 membered heterocycloalkyl are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R³²;    -   or any R^(c31) and R^(d31) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R³²;    -   each R^(h31) and R^(i31) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h31) and R^(i31) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a32), R^(b32), R^(c32) and R^(d32), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆        haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆        alkynyl are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R^(g);    -   each R^(h32) and R^(i32) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h32) and R^(i32) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a50), R^(b50), R^(c50) and R^(b50), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl;        wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁵¹;    -   or any R^(c50) and R^(d50) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R⁵¹;    -   each R^(h50) and R^(i50) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h50) and R^(i50) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a51), R^(b51), R^(c51) and R^(d51), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl and 4-7 membered heterocycloalkyl are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁵²;    -   or any R^(c51) and R^(d51) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R⁵²;    -   each R^(h51) and R^(i51) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h51) and R^(i51) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a52), R^(b52), R^(c52) and R^(d52), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆        haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆        alkynyl are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R^(g);    -   each R^(h52) and R^(i52) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h52) and R^(i32) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a60), R^(b60), R^(c60) and R^(d60), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl;        wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R^(g);    -   or any R^(c60) and R^(d60) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R^(g);    -   each R^(h60) and R^(i60) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h60) and R^(i60) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a70), R^(b70), R^(c70) and R^(d70) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R⁷¹;    -   or any R^(c70) and R^(d70) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R⁷¹;    -   each R^(h70) and R^(i70) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h70) and R^(i70) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a71), R^(b71), R^(c71) and R^(d71), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl and 4-7 membered heterocycloalkyl are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁷²;    -   or any R^(c71) and R^(d71) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R⁷²;    -   each R^(h7)1 and R^(i71) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h71) and R^(i71) attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl;    -   each R^(a72), R^(b72), R^(c72) and R^(d72), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆        haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆        alkynyl are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R^(g);    -   each R^(h72) and R^(i72) is independently selected from OH, C₁₋₆        alkoxy, and C₁₋₆ haloalkoxy; or any R^(h72) and R^(i7)2 attached        to the same B atom, together with the B atom to which they are        attached, form a 5- or 6-membered heterocycloalkyl group        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from C₁₋₆ alkyl and C₁₋₆ haloalkyl; and    -   each R^(g) is independently selected from D, OH, NO₂, CN, halo,        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆        cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆        haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy,        HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl,        amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆        alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,        C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆        alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino,        C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkylcarbonyloxy,        aminocarbonyloxy, C₁₋₆ alkylaminocarbonyloxy, di(C₁₋₆        alkyl)aminocarbonyloxy, C₁₋₆ alkylsulfonylamino, aminosulfonyl,        C₁₋₆ alkylaminosulfonyl, di(C₁₋₆alkyl)aminosulfonyl,        aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆        alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆        alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In an embodiment of Formula I, X is CR⁷. In another embodiment, X is N.

In an embodiment, Y is O. In another embodiment, Y is C(R⁵)₂. In yetanother embodiment, Y is C═O. In still another embodiment, Y is NR^(5N).

In an embodiment, W is C═O. In another embodiment, W is C(R⁸)₂.

In an embodiment, Z is C(R⁹)₂. In another embodiment, Z is O. In yetanother embodiment, Z is NR^(9N). In still another embodiment Z is abond.

In an embodiment,

represents a double bond, and R³ is absent. In another embodiment,

represents a single bond. In yet another embodiment,

represents a single bond, and R⁴ is ═O. In still another embodiment,

represents a single bond, and R⁴ is ═S.

In another embodiment of Formula I,

-   -   represents a double bond;    -   X is CR⁷ or N;    -   Y is NR^(5N) or C═O;    -   W is C═O, or C(R⁸)₂;    -   Z is O, NR^(9N), or a bond;    -   R¹ and R² are each independently selected from H, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, halo, and CN;    -   Cy is C₆₋₁₀ aryl or 5-10 membered heteroaryl, both of which are        optionally substituted with 1, 2, 3 or 4 substituents        independently selected from R¹⁰;    -   R³ absent;    -   R⁴ is selected from H, C₁₋₆ alkyl, and OR^(a3), wherein alkyl is        optionally substituted one or two times with R³⁰;    -   R^(5N) is H or C₁₋₆ alkyl;    -   R⁵ and R⁸ are each independently selected from H, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, halo, D, and CN;    -   ring A is 4-7 membered heterocycloalkyl;    -   n is 1 or 2;    -   R is selected from C₁₋₆ alkyl, halo, D, CN, C(O)R^(b),        C(O)OR^(a), and OC(O)R^(b);    -   R⁷ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, and        CN;    -   R^(9N) is H or C₁₋₆ alkyl;    -   each R¹⁰ is independently selected from C₁₋₆ alkyl, halo, and        OR^(a10);    -   each R³⁰ is 4-10 membered heterocycloalkyl optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R³¹;    -   each R³¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, and CN;    -   R^(a3) is C₁₋₆ alkyl optionally substituted one or two times        with R³⁰;    -   each R^(a)B and R^(b)B is independently selected from H, C₁₋₆        alkyl, and C₂₋₆ alkenyl; and    -   R^(a10) is H or C₁₋₆ alkyl.

In another embodiment of Formula I,

-   -   represents a double bond;    -   X is CR⁷;    -   Y is NR^(5N) or C═O;    -   W is C═O, or C(R⁸)₂;    -   Z is O, NR^(9N), or a bond;    -   R¹ and R² are each independently H or halo;    -   Cy is C₆₋₁₀ aryl or 5-10 membered heteroaryl, both of which are        optionally substituted with 1, 2, 3 or 4 substituents        independently selected from R¹⁰;    -   R³ is absent;    -   R⁴ is selected from H, C₁₋₆ alkyl, and OR^(a3), wherein alkyl is        optionally substituted one or two times with R³⁰;    -   R^(5N) is H or C₁₋₆ alkyl;    -   each R⁵ and R⁸ are H;    -   ring A is 4-6 membered heterocycloalkyl;    -   n is 1;    -   R⁶ is C(O)R^(b6);    -   R⁷ is halo;    -   R^(9N) is H;    -   each R¹⁰ is independently selected from C₁₋₆ alkyl, halo, and        OR^(a10);    -   each R³⁰ is 4-10 membered heterocycloalkyl optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R³¹;    -   each R³¹ is C₁₋₆ alkyl;    -   R^(a3) is C₁₋₆ alkyl optionally substituted one or two times        with R³⁰;    -   each R^(b6) is C₂₋₆ alkenyl; and    -   R^(a10) is H or C₁₋₆ alkyl.

In an embodiment, the compound of Formula I is a compound of Formula Ia:

-   -   or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I is a compound ofFormula Ib:

-   -   or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the compound of Formula I is a compound ofFormula Ic:

-   -   or a pharmaceutically acceptable salt thereof.

In an embodiment, the compound of Formula I is a compound of FormulaII′:

-   -   or a pharmaceutically acceptable salt thereof.

In an embodiment of Formula II′,

-   -   X is N or CR⁷;    -   Y is NR^(5N), or C═O;    -   W is C═O, or C(R⁸)₂;    -   Z is O, NR^(9N), O(R⁹)₂, or a bond;    -   R¹ and R² are each independently selected from H, D, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a),        SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),        OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),        NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)₂R^(b),        NR^(c)S(O)₂NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d),        wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, are        each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R^(g);    -   Cy is selected from C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;        wherein the 4-10 membered heterocycloalkyl and 5-10 membered        heteroaryl each has at least one ring-forming carbon atom and 1,        2, 3, or 4 ring-forming heteroatoms independently selected from        N, O, and S; wherein the N and S are optionally oxidized;        wherein a ring-forming carbon atom of 5-10 membered heteroaryl        and 4-10 membered heterocycloalkyl is optionally substituted by        oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl are each optionally substituted with 1, 2, 3 or 4        substituents independently selected from R¹⁰;    -   R⁴ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a3), SR^(a3),        C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), C(O)R^(b3),        OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(3c)C(O)R^(b3),        NR^(3c)C(O)OR^(a3), NR^(c3)C(O)NR^(c3)R^(d3),        NR^(c3)S(O)₂R^(b3), NR^(c1)S(O)₂NR^(c3)R^(d3), S(O)₂R^(b3), and        S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,        4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R³⁰;    -   R^(5N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl;        wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, 4-10 membered heterocycloalkyl, C₀₋₁₀ aryl, and 5-10        membered heteroaryl, are each optionally substituted with 1, 2,        3, or 4 substituents independently selected from R⁵⁰;    -   each R⁵ and R⁸ are independently selected from H, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, halo, D, CN, OR^(a5), SR^(a5), C(O)R^(b),        C(O)NR^(c5)R^(d5), (O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),        NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),        NR^(c5)C(O)NR^(c5)R^(d5), NR^(c4)S(O)₂R^(b5),        NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5);        wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10        membered heteroaryl, are each optionally substituted with 1, 2,        3, or 4 substituents independently selected from R⁵⁰;    -   ring A is C₃₋₁₄ cycloalkyl or 4-14 membered heterocycloalkyl;        wherein the 4-14 membered heterocycloalkyl has at least one        ring-forming carbon atom and 1, 2, 3, or 4 ring-forming        heteroatoms independently selected from N, O, and S; wherein the        N and S are optionally oxidized; wherein a ring-forming carbon        atom of 4-14 membered heterocycloalkyl is optionally substituted        by oxo to form a carbonyl group;    -   n is 0, 1, 2, 3, or 4;    -   each R⁶ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered        heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a6), SR^(a6),        C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6),        OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),        NR^(c6)C(O)OR^(a6), NR⁶C(O)NR^(c6)R^(d6), NR^(c6)S(O)₂R^(b6),        NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6);        wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10        membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10        membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R⁶⁰;    -   R⁷ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D,        CN, OR^(a7), SR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7), (O)OR^(a7),        OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7),        NR^(c7)C(O)R^(b7), NR⁷C(O)OR^(a7), NR⁷C(O)NR^(c7)R^(d7),        NR⁷S(O)₂R^(b7), NR⁷S(O)₂NR^(c7)R^(d7), S(O)₂R^(b7), and        S(O)₂NR^(c7)R^(d7); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀        aryl, and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁷⁰;    -   R^(9N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl, are each optionally substituted with        1, 2, 3, or 4 substituents independently selected from R^(g);    -   each R⁹ is independently selected from selected from H, D, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆        cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7 membered        heterocycloalkyl, halo, CN, OR^(a9), SR^(a9), C(O)R^(b9),        C(O)NR^(c9)R^(d9), (O)OR^(a9), OC(O)R^(b9), OC(O)NR^(c9)R^(d9),        NR^(c9)R^(d9), NR^(c9)C(O)R^(b9), NR^(c9)C(O)OR^(a9),        NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)₂R^(b9),        NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)₂R^(b9), and S(O)₂NR^(c9)R^(d9);    -   each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a10),        SR^(a10), C(O)R^(b10), C(O)NR^(c1)R^(d10),        C(O)OR^(a10)(O)R^(b10), OC(O)NR^(c10)R^(d10), NR^(c10)R^(d10),        NR^(c10)C(O)R^(b10), NR^(c10)C(O)OR^(a10), NR^(c10),        C(O)NR^(c10)R^(d10), NR^(c10)S(O)₂R^(b10),        NR^(c10)S(O)₂NR^(c10)R^(d10), S(O)R^(b10), S(O)NR^(c10)R^(d10),        S(O)₂R^(b10), and S(O)₂NR^(c10)R^(d10); wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀        cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃        alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered        heteroaryl-C₁₋₃ alkylene are each optionally substituted with 1,        2, 3, or 4 substituents independently selected from R¹¹;    -   each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        halo, D, CN, OR^(a11), SR^(a11), C(O)R^(b11),        C(O)NR^(c11)R^(d11), C(O)OR^(a11), OC(O)R^(b11),        OC(O)NR^(c11)R^(d11), NR^(c11)R^(d11), NR^(c11)C(O)R^(b11),        NR^(c11)C(O)OR^(a11), NR^(c11)C(O)NR^(c11)R^(d11),        NR^(c11)S(O)₂R^(b11), NR^(c11)S(O)₂NR^(c11)R^(d11),        S(O)₂R^(b11), and S(O)₂NR^(c11)R^(d11);    -   each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a30),        SR^(a30), C(O)R^(b30), C(O)NR^(c30)R^(d30), C(O)OR^(a30),        OC(O)R^(b30), OC(O)NR^(c30)R^(d30), NR^(c30)R^(d30),        NR^(c30)C(O)R^(b30), NR^(c30)C(O)OR^(a30),        NR^(c30)C(O)NR^(c30)R^(b30), NR^(c30)(O)₂R^(b30),        NR^(c30)S(O)₂NR^(c30)R^(d30); S(O)₂R^(b30), and        S(O)₂NR^(c30)R^(d30); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃        alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀        aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene        are each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R³¹;    -   each R³¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        halo, D, CN, OR^(a31), SR^(a31), C(O)R^(b31),        C(O)NR^(c31)R^(d31), C(O)OR^(a31), OC(O)R^(b31),        OC(O)NR^(c31)R^(d31), NR^(c31)R^(d31), NR^(c1)C(O)R^(b31),        NR^(c1)C(O)OR^(a31), NR^(c31)C(O)NR^(c31)R^(d31),        NR^(c31)S(O)₂R^(b31), NR^(c31)S(O)₂NR^(c31)R^(d31),        S(O)₂R^(b31), and S(O)₂NR^(c1)R^(d31); wherein said C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl, are        each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R³²;    -   each R³² is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl,        5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo, D,        CN, OR^(a32), SR^(a32), C(O)R^(b32), C(O)NR^(c32)R^(d32),        C(O)OR^(a32), OC(O)R^(b32), OC(O)NR^(c32)R^(d32),        NR^(c32)R^(d32), NR^(c32)C(O)R^(d32), NR^(c2)C(O)OR^(a32),        NR^(c32)C(O)NR^(c32)R^(d32), NR^(c32)S(O)₂R^(b32),        NR^(c32)S(O)₂NR^(c32)R^(d32), S(O)₂R^(b32), and        S(O)₂NR^(c32)R^(d32);    -   each R⁵⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10        membered heteroaryl-C₁₋₃ alkylene, halo, D, CN, OR^(a50),        SR^(a50), C(O)R^(b50), C(O)NR^(c50)R^(d50), C(O)OR^(a50),        OC(O)R^(b50), OC(O)NR^(c50)R^(d50), NR^(c50)R^(d50),        NR^(c50)C(O)R^(b50), NR^(c50)C(O)OR^(a50),        NR^(c50)C(O)NR^(c50)R^(d50), NR^(c50)S(O)₂R^(b50),        NR^(c50)S(O)₂NR^(c50)R^(d5), S(O)₂R^(b50), and        S(O)₂NR^(c50)R^(d50);    -   each R⁶⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        halo, D, CN, OR^(a60), SR^(a60), C(O)R^(b60),        C(O)NR^(c60)R^(d60), C(O)OR^(a60), OC(O)R^(b60),        OC(O)NR^(c60)R^(d60), NR^(c60)R^(d60), NR^(c60)C(O)R^(b60),        NR^(c60)C(O)OR^(a60), NR^(c60)C(O)NR^(c60)R^(d60);        NR^(c60)S(O)₂R^(b60), NR^(c60)S(O)₂NR^(c60)R^(d60),        S(O)₂R^(b60), and S(O)₂NR^(c60)R^(d60);    -   each R⁷⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        halo, D, CN, OR^(a70), SR^(a70), C(O)R^(b70),        C(O)NR^(c70)R^(d70), C(O)OR^(a70), OC(O)R^(b70);        OC(O)NR^(c70)R^(d70), NR^(c70)R^(d70), NR^(c70)C(O)R^(b70),        NR^(c70)C(O)OR^(a7), NR^(c7)C(O)NR^(c70)R^(d70),        NR^(c70)S(O)₂R^(b70), NR^(c70)S(O)₂NR^(c70)R^(d70),        S(O)₂R^(b70), and S(O)₂NR^(c70)R^(d70);    -   each R^(a), R^(b), R^(c), and R^(d) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7        membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, and 4-7 membered heterocycloalkyl, are each        optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R^(g);    -   or any R^(c) and R^(d) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R^(g);    -   each R^(a3), R^(b3), R^(c3) and R^(d3) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,        5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10        membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃        alkylene, and 5-10 membered heteroaryl-C₁₋₃ alkylene; wherein        said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,        4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered        heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, and        5-10 membered heteroaryl-C₁₋₃ alkylene, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R³⁰;    -   or any R^(c3) and R^(d3) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R³⁰;    -   each R^(a5), R^(b5), R^(c5) and R^(d5) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁵⁰;    -   or any R^(c5) and R^(d5) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R⁵⁰;    -   each R^(a6), R^(b6), R^(c6) and R^(d6) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁶⁰;    -   or any R^(c6) and R^(d6) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R⁶⁰;    -   each R^(a7), R^(b7), R^(c7) and R^(d7) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and        5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R⁷⁰;    -   or any R^(c7) and R^(d7) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R⁷⁰;    -   each R^(a9), R^(b9), R^(c9), and R^(d9) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and        4-7 membered heterocycloalkyl;    -   or any R^(c9) and R^(d9) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group;    -   each R^(a10), R^(b10), R^(c10) and R^(d10) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R¹¹;    -   or any R^(c10) and R^(d10) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R¹¹;    -   each R^(a11), R^(b11), R^(c11) and R^(d11), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl;    -   or any R^(c11) and R^(d11) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group;    -   each R^(a30), R^(b30), R^(c30) and R^(d30) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R³¹;    -   or any R^(c30) and R^(d30) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R³¹;    -   each R^(a31), R^(b31), R^(c31) and R^(d31), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl and 4-7 membered heterocycloalkyl are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R³²;    -   or any R^(c1) and R^(d3)1 attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2 or 3 substituents independently selected from R³²;    -   each R^(a32), R^(b32), R^(c32) and R^(d32), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆        haloalkyl;    -   each R^(a50), R^(b50), R^(c50) and R^(d50), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl;    -   or any R^(c50) and R^(d50) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group;    -   each R^(a60), R^(b60), R^(c60) and R^(d60), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl;    -   or any R^(c60) and R^(d60) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group;    -   each R^(a70), R^(b70), R^(c70) and R^(d70) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl;    -   or any R^(c70) and R^(d7) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group; and    -   each R^(g) is independently selected from D, OH, NO₂, CN, halo,        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆        cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆        haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy,        HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl,        amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆        alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl,        C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆        alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylcarbonylamino,        C₁₋₆ alkoxycarbonylamino, C₁₋₆ alkylcarbonyloxy,        aminocarbonyloxy, C₁₋₆ alkylaminocarbonyloxy, di(C₁₋₆        alkyl)aminocarbonyloxy, C₁₋₆ alkylsulfonylamino, aminosulfonyl,        C₁₋₆ alkylaminosulfonyl, di(C₁₋₆alkyl)aminosulfonyl,        aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆        alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆        alkylaminocarbonylamino, and di(C₁₋₆alkyl)aminocarbonylamino.

In an embodiment, the compound of Formula I is a compound of Formula II:

-   -   or a pharmaceutically acceptable salt thereof.

In an embodiment of Formulas I and II,

-   -   Y is NR^(5N), or C═O;    -   W is C═O, or C(R⁸)₂;    -   Z is O, NR^(9N), or a bond;    -   R¹ and R² are each independently selected from H, D, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, halo, CN, OR^(a), and NR^(c)R^(d);    -   Cy is C₆₋₁₀ aryl or 5-10 membered heteroaryl; wherein the 5-10        membered heteroaryl each has at least one ring-forming carbon        atom and 1, 2, 3, or 4 ring-forming heteroatoms independently        selected from N, O, and S; wherein a ring-forming carbon atom of        5-10 membered heteroaryl is optionally substituted by oxo to        form a carbonyl group; and wherein the C₆₋₁₀ aryl and 5-10        membered heteroaryl are each optionally substituted with 1, 2, 3        or 4 substituents independently selected from R¹⁰;    -   R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀        cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10        membered heteroaryl, halo, D, CN, OR^(a3), C(O)R^(b3),        C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),        NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), and S(O)₂R^(b3); wherein said        C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl, and 5-10 membered heteroaryl, are each optionally        substituted with 1, 2, 3, or 4 substituents independently        selected from R³⁰;    -   R^(5N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, and C₁₋₆ haloalkyl;    -   each R⁵ and R⁸ are independently selected from H, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, halo, D, CN, OR^(a5), and NR^(c5)R^(d5);    -   ring A is C₃₋₆ cycloalkyl or 4-7 membered heterocycloalkyl;        wherein the 4-7 membered heterocycloalkyl has at least one        ring-forming carbon atom and 1, 2, 3, or 4 ring-forming        heteroatoms independently selected from N, O, and S; wherein a        ring-forming carbon atom of 4-6 membered heterocycloalkyl is        optionally substituted by oxo to form a carbonyl group;    -   n is 0, 1, or 2;    -   each R⁶ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,        C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, OR^(a), C(O)R^(b),        C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),        NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), and S(O)₂R^(b6); R⁷ is        selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, CN,        OR^(a7), and NR^(c7)R^(d7);    -   R^(9N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, and C₁₋₆ haloalkyl;    -   each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, OR^(a10),        and NR^(c10)R^(d10);    -   each R³⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,        halo, D, CN, OR^(a30), C(O)R^(b30), C(O)NR^(c30)R^(d30),        C(O)OR^(a30), OC(O)R^(b30), OC(O)NR^(c30)R^(d30),        NR^(c30)R^(d30), NR^(c30), C(O)R^(b30), and S(O)₂R^(b30);        wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, 4-10 membered heterocycloalkyl, C₃₋₁₀ aryl, and 5-10        membered heteroaryl, are each optionally substituted with 1, 2,        3, or 4 substituents independently selected from R³¹;    -   each R³¹ is independently selected from C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN, OR^(a31),        and NR^(c31)R^(d31);    -   each R^(a), R^(c), and R^(d) is independently selected from H,        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;    -   each R^(a3), R^(b3), R^(c3) and R^(d3) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,        C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₃₋₁₀ aryl,        and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered        heterocycloalkyl, C₃₋₁₀ aryl, and 5-10 membered heteroaryl, are        each optionally substituted with 1, 2, 3, or 4 substituents        independently selected from R³⁰;    -   or any R^(c3) and R^(d3) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R³⁰;    -   each R^(a5), R^(c5) and R^(d5) is independently selected from H,        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;    -   each R^(a6), R^(b6), R^(c6) and R^(d6) is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆        haloalkyl;    -   each R^(a7), R^(b7) and R^(d7) is independently selected from H,        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;    -   each R^(a10), R^(b10), R^(c10) and R^(d10) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and        C₁₋₆ haloalkyl;    -   each R^(a11), R^(b11), R^(c11) and R^(d11), is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and        4-7 membered heterocycloalkyl;    -   each R^(a30), R^(b30), R^(c30) and R^(d30) is independently        selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆        haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,        C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein said C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10        membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered        heteroaryl, are each optionally substituted with 1, 2, 3, or 4        substituents independently selected from R³¹;    -   or any R^(c30) and R^(d30) attached to the same N atom, together        with the N atom to which they are attached, form a 4-, 5-, 6- or        7-membered heterocycloalkyl group optionally substituted with 1,        2, 3, or 4 substituents independently selected from R³¹; and    -   each R^(a31), R^(c31) and R^(d31), is independently selected        from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆        haloalkyl.

In an embodiment, the compound of Formula I or II is a compound ofFormula IIa:

-   -   or a pharmaceutically acceptable salt thereof.

In an embodiment of Formula IIa,

-   -   R¹ and R² are each independently H or halo;    -   Cy is C₆₋₁₀ aryl or 5-10 membered heteroaryl, both of which are        optionally substituted one, two, or three times with R¹⁰;    -   R⁴ is selected from H, C₁₋₆ alkyl, and OR^(a3), wherein alkyl is        optionally substituted one or two times with R³⁰;    -   R^(5N) is H or C₁₋₆ alkyl;    -   ring A is 4-6 membered heterocycloalkyl;    -   n is 1;    -   R¹ is C(O)R^(b6);    -   R⁷ is halo;    -   R^(9N) is H;    -   each R¹⁰ is independently selected from C₁₋₆ alkyl, halo, and        OR^(a10);    -   each R³⁰ is 4-6 membered heterocycloalkyl optionally substituted        one or two times with R³¹;    -   each R³¹ is C₁₋₆ alkyl;    -   R^(a3) is C₁₋₆ alkyl optionally substituted one or two times        with R³⁰;    -   each R^(b)s is C₂₋₆ alkenyl; and    -   R^(a10) is H or C₁₋₆ alkyl.

In another embodiment, the compound of Formula I or II is a compound ofFormula IIb:

-   -   or a pharmaceutically acceptable salt thereof.

In an embodiment of Formula IIb,

-   -   R¹ and R² are each independently H or halo;    -   Cy is C₃₋₁₀ aryl or 5-10 membered heteroaryl, both of which are        optionally substituted one, two, or three times with R¹⁰;    -   R⁴ is selected from H, C₁₋₆ alkyl, and OR^(a3), wherein alkyl is        optionally substituted one or two times with R³⁰;    -   R^(5N) is H or C₁₋₆ alkyl;    -   each R⁵ and R⁸ are H;    -   ring A is 4-6 membered heterocycloalkyl;    -   n is 1;    -   R⁶ is C(O)R^(b6);    -   R⁷ is halo;    -   each R¹⁰ is independently selected from C₁₋₆ alkyl, halo, and        OR^(a10);    -   each R³⁰ is 4-6 membered heterocycloalkyl optionally substituted        one or two times with R³¹;    -   each R³¹ is C₁₋₆ alkyl;    -   R^(a3) is C₁₋₆ alkyl optionally substituted one or two times        with R³⁰;    -   each R^(b6) is C₂₋₆ alkenyl; and    -   R^(a10) is H or C₁₋₆ alkyl.

In yet another embodiment, the compound of Formula I or II is a compoundof Formula IIc:

-   -   or a pharmaceutically acceptable salt thereof.

In an embodiment of Formula IIc,

-   -   R¹ and R² are each independently H or halo;    -   Cy is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl both        of which are optionally substituted with one, two, or three R¹⁰;    -   R⁴ is selected from H, C₁₋₆ alkyl, and OR^(a3), wherein alkyl is        optionally substituted one or two times with R³⁰;    -   ring A is 4-6 membered heterocycloalkyl;    -   n is 1;    -   R⁶ is C(O)R^(b6);    -   R⁷ is halo;    -   both R⁸ are H;    -   each R¹⁰ is independently selected from C₁₋₆ alkyl, halo, and        OR^(a10);    -   each R³⁰ is 4-6 membered heterocycloalkyl optionally substituted        one or two times with R³¹;    -   each R³¹ is C₁₋₆ alkyl;    -   R^(a3) is C₁₋₆ alkyl optionally substituted one or two times        with R³⁰;    -   each R^(b6) is C₂₋₆ alkenyl; and    -   R^(a10) is H or C₁₋₆ alkyl.

In an embodiment of any of the Formulae disclosed herein, R¹ is selectedfrom H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo,CN, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a),NR^(c)C(O)NR^(c)R^(d), NR^(c)S(O)₂R^(b), S(O)₂R^(b), andS(O)₂NR^(c)R^(d); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, are each optionally substituted with 1 or 2 substituentsindependently selected from R^(g).

In another embodiment, R¹ is selected from H, D, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), (O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)₂R^(b), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In an embodiment of any of the Formulae disclosed herein, R¹ is selectedfrom H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo,CN, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(d1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)₂R^(b1),S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl, are each optionally substituted with 1 or 2substituents independently selected from R^(g).

In another embodiment, R¹ is selected from H, D, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a1), SR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1),OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(d1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), NR^(c1)S(O)₂R^(b1),S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1).

In yet another embodiment, R¹ is selected from H, D, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, and CN. In still anotherembodiment, R¹ is selected from H, D, and C₁₋₃ alkyl. In anotherembodiment, R¹ is H.

In an embodiment, R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), (O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)₂R^(b), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, are each optionally substitutedwith 1 or 2 substituents independently selected from R^(g).

In another embodiment, R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a), SR^(a),C(O)R^(b), C(O)NR^(c)R^(d), (O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d),NR^(c)S(O)₂R^(b), S(O)₂R^(b), and S(O)₂NR^(c)R^(d).

In an embodiment, R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), (O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(d2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), NR²S(O)₂R^(b2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, are each optionally substituted with 1 or 2 substituentsindependently selected from R²⁰.

In another embodiment, R² is selected from H, D, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), (O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(d2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), NR²S(O)₂R^(b2),S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2).

In yet another embodiment, R² is selected from H, D, C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, and CN. In another embodiment, R² is selected from C₁₋₆alkyl and halo. In still another embodiment, R² is halo. In anotherembodiment, R² is chloro.

In an embodiment, Cy is selected from C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the4-10 membered heterocycloalkyl and 5-10 membered heteroaryl each has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein a ring-forming carbon atom of 6-10membered heteroaryl and 4-10 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰.

In another embodiment, Cy is selected from C₆₋₁₀ aryl and 5-10 memberedheteroaryl; wherein the 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, or 3 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl is optionally substituted by oxo to form a carbonyl group;and wherein the C₆₋₁₀ aryl and 6-10 membered heteroaryl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹⁰.

In yet another embodiment, Cy is selected from phenyl, naphthalenyl andindazolyl; wherein the phenyl, naphthalenyl and indazolyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹⁰. In an embodiment, each R¹⁰ is independently selectedfrom C₁₋₆ alkyl, halo, OR^(a10). In another embodiment, R^(a10) is H orC₁₋₆ alkyl.

In an embodiment, Cy is selected from 2-fluoro-6-hydroxyphenyl,2-chloro-5-hydroxy-phenyl, 5-methyl-1H-indazol-4-yl,3-methyl-1H-indazol-4-yl, and 2-fluoro-6-methoxyphenyl.

In another embodiment, Cy is 2-fluoro-6-hydroxyphenyl. In yet anotherembodiment, Cy is 2-chloro-5-hydroxy-phenyl. In still anotherembodiment, Cy is 5-methyl-1H-indazol-4-yl.

In another embodiment, Cy is 3-methyl-1H-indazol-4-yl. In yet anotherembodiment, Cy is 2-fluoro-6-methoxyphenyl.

In an embodiment, R³N

CR⁴ is a single bond, and R⁴ is ═O. In another embodiment, R³N

CR⁴ is a single bond, and R⁴ is ═S. In yet another embodiment, R³N

CR⁴ is a double bond, and R³ is absent.

In an embodiment, R³ is selected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl, wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl, areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from R³⁰.

In another embodiment, R³ is selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl.

In an embodiment, R⁴ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),OC(O)R^(b3), OC(O)NR^(c3)R^(d3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3),NR^(c3)C(O)OR^(a3), NR³C(O)NR^(c3)R^(d3), NR³S(O)₂R^(b3), S(O)₂R^(b3),and S(O)₂NR^(c3)R^(d3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R³⁰.

In another embodiment, R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, halo, D, CN, OR^(a3), C(O)R^(b3),C(O)NR^(c3)R^(d3), C(O)OR^(a3), OC(O)R^(b3), OC(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), and S(O)₂R^(b3); wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and5-10 membered heteroaryl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R³⁰.

In yet another embodiment, R⁴ is selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, D, CN, OR^(a3), and NR^(c3)R^(d3); wherein said C₁₋₆alkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 memberedheteroaryl, are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R³⁰.

In still another embodiment, R⁴ is selected from H, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and OR^(a3); wherein said 4-10 memberedheterocycloalkyl, and C₆₋₁₀ aryl, are each optionally substituted with 1or 2 substituents independently selected from R³.

In another embodiment, R⁴ is selected from H, 4-6 memberedheterocycloalkyl, and OR^(a3); wherein said 4-6 memberedheterocycloalkyl is optionally substituted with 1 or 2 substituentsindependently selected from R³⁰.

In an embodiment, R⁴ is selected from H,1-(methyl-pyrrolidin-2-yl)methoxy, and N-(ethoxy)piperidine. In anotherembodiment, R⁴ is H. In yet another embodiment, R⁴ is1-(methyl-pyrrolidin-2-yl)methoxy. In still another embodiment, R⁴ isN-(ethoxy)piperidine. In another embodiment, R⁴ is3-(dimethylamino)-azetidin-1-yl.

In an embodiment, R^(5N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R⁵⁰.

In another embodiment, R^(5N) is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl. In yetanother embodiment, R^(5N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₁₋₆ haloalkyl.

In still another embodiment, R^(5N) is H. In another embodiment, R^(5N)is methyl. In an embodiment, each R⁵ and R⁸ is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, D, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c3)R^(d5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₁₋₆ aryl, and 5-10 membered heteroaryl, are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R⁵.

In another embodiment, each R⁵ and R⁸ is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, D, CN, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), OC(O)R^(b5), OC(O)NR^(c5)R^(d5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5),NR^(c5)C(O)NR^(c5)R^(d5), NR⁵S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5),S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5).

In yet another embodiment, each R⁵ and R⁸ is independently selected fromH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN,and OR^(a).

In another embodiment each R⁵ is independently selected from H and C₁₋₆alkyl. In another embodiment each R⁵ is H. In another embodiment each R⁸is independently selected from H and C₁₋₆ alkyl. In another embodimenteach R⁸ is H.

In an embodiment, ring A is C₃₋₁₀ cycloalkyl or 4-10 memberedheterocycloalkyl; wherein the 4-10 membered heterocycloalkyl has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein a ring-forming carbon atom of 4-10membered heterocycloalkyl is optionally substituted by oxo to form acarbonyl group.

In another embodiment, ring A is C₃₋₆ cycloalkyl or 4-6 memberedheterocycloalkyl; wherein the 4-6 membered heterocycloalkyl has at leastone ring-forming carbon atom and 1 or 2 ring-forming heteroatomsindependently selected from N and O.

In another embodiment, ring A is 4-10 membered heterocycloalkyl; whereinthe 4-10 membered heterocycloalkyl has at least one ring-forming carbonatom and 1, 2, 3, or 4 ring-forming heteroatoms independently selectedfrom N, O, and S. In yet another embodiment, ring A is 4-7 memberedheterocycloalkyl. In another embodiment, ring A is 4-6 memberedheterocycloalkyl. In yet another embodiment, ring A is piperidine. Instill another embodiment, ring A is azetidine. In an embodiment, ring Ais pyrrolidine.

In another embodiment, ring A is C₃₋₁₀ cycloalkyl. In anotherembodiment, ring A is C₃₋₆ cycloalkyl.

In still another embodiment, n is 1, 2, or 3. In another embodiment, nis 0, 1, or 2. In yet another embodiment, n is 0 or 1. In anotherembodiment, n is 1. In still another embodiment, n is 0.

In an embodiment, each R⁶ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b8), C(O)NR^(c6)R^(d8),C(O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(6c)C(O)OR^(a6), NR^(c6)C(O)NR^(c6)R^(d6),NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6),S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R⁶⁰.

In another embodiment, each R⁶ is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, D, CN, NO₂, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), (O)OR^(a6), OC(O)R^(b6), OC(O)NR^(c6)R^(d6),NR^(c6)R^(d6), NR^(c6)C(O)R^(b6), NR⁶C(O)OR^(a6),NR^(c6)C(O)NR^(c6)R^(d6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6).

In yet another embodiment, each R⁶ is independently selected fromC(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), OC(O)R^(b6), andOC(O)NR^(c6)R^(d6). In another embodiment, each R⁶ is independentlyselected from C₁₋₆ alkyl, and C(O)R^(b6). In another embodiment, each R⁶is C(O)R^(b6).

In another embodiment, each R⁶ is independently selected from C(O)R^(b6)and NR^(c6)R^(d6). In another embodiment, each R⁶ is NR^(c6)R^(d6).

In an embodiment, ring A-R⁶ is selected from4,4-(piperidin-1-yl)prop-2-en-1-one,3,3-(piperidin-1-yl)prop-2-en-1-one, 3,3-(azetidin-1-yl)prop-2-en-1-one,and 3,3-(pyrrolidin-1-yl)prop-2-en-1-one. In another embodiment, ringA-R⁶ is 4,4-(piperidin-1-yl)prop-2-en-1-one.

In yet another embodiment, ring A-R⁶ is3,3-(piperidin-1-yl)prop-2-en-1-one. In still another embodiment, ringA-R⁶ is 3,3-(azetidin-1-yl)prop-2-en-1-one. In another embodiment, ringA-R⁶ is 3,3-(pyrrolidin-1-yl) prop-2-en-1-one.

In yet another embodiment, ring A-R⁶ is selected from:

In an embodiment, ring A-R⁶ is A-1. In another embodiment, ring A-R⁶ isA-2. In yet another embodiment, ring A-R⁶ is A-3. In still anotherembodiment, ring A-R⁶ is A-4.

In an embodiment, ring A-R⁶ is selected from:

In an embodiment, ring A-R⁶ is A-1a. In another embodiment, ring A-R⁶ isA-2a. In yet another embodiment, ring A-R⁶ is A-3a. In still anotherembodiment, ring A-R⁶ is A-4a. In an embodiment, ring A-R⁶ is selectedfrom A-1a, A-2a, A-3a, and A-4a; wherein R⁶ is H.

In an embodiment, R⁷ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and 4-6 memberedheterocycloalkyl, halo, D, CN, OR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7),C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)NR^(c7)S(O)₂R^(b7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, and 4-6membered heterocycloalkyl, are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R⁷⁰.

In another embodiment, R⁷ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, and 4-6 memberedheterocycloalkyl, halo, D, CN, OR^(a7), C(O)R^(b7), C(O)NR^(c7)R^(d7),C(O)OR^(a7), OC(O)R^(b7), OC(O)NR^(c7)R^(d7), NR^(c7)R^(d7),NR^(c7)C(O)R^(b7), NR^(c7)C(O)OR^(a7), NR^(c7)C(O)NR^(c7)R^(d7)NR⁷S(O)₂R^(b7), S(O)₂R^(b7), and S(O)₂NR^(c7)R^(d7).

In yet another embodiment, wherein R⁷ is selected from H, D, C₁₋₆ alkyl,C₁₋₆ haloalkyl, halo, and CN. In still another embodiment, R⁷ is halo.In another embodiment, R⁷ is fluoro.

In an embodiment, R^(9N) is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g).

In another embodiment, R^(9N) is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl. In yet another embodiment,R^(9N) is H.

In an embodiment, each R⁹ is independently selected from H, D, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo,CN, OR^(a9), SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), (O)OR^(a9),OC(O)R^(b9), OC(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)C(O)OR^(a9), NR^(c9)C(O)NR^(c9)R^(d9), NR^(c9)S(O)R^(b9),NR^(c9)S(O)₂R^(b9), NR^(c9)S(O)₂NR^(c9)R^(d9), S(O)R^(b9),S(O)NR^(c9)R^(d9), S(O)₂R^(b9), and S(O)₂NR^(c9)R^(d9).

In another embodiment, each R⁹ is independently selected from H, D, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, halo,CN, OR^(a9), SR^(a9), C(O)R^(b9), C(O)NR^(c9)R^(d9), (O)OR^(a9),OC(O)R^(b9), OC(O)NR^(c9)R^(d9), NR^(c9)R^(d9), NR^(c9)C(O)R^(b9),NR^(c9)S(O)₂R^(b9), S(O)₂R^(b9), and S(O)₂NR^(c9)R^(d9).

In an embodiment, each R⁹ is independently selected from H, D, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl. In an embodiment,each R⁹ is independently selected from H, D, and C₁₋₆ alkyl. In anembodiment, each R⁹ is H.

In an embodiment, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a10), SR^(a10), C(O)R^(b10), C(O)NR^(c10)R^(d10),C(O)OR^(a10), C(O)R^(b10), OC(O)NR^(c10)R^(d10), NR^(c10)R^(d10),NR^(c10), C(O)R^(b10), NR^(c10), C(O)OR^(a10), NR^(c10),C(O)NR^(c10)R^(d10), NR^(c10)S(O)₂R^(b10), NR^(c10)S(O)₂NR^(c10)R^(d10),S(O)R^(b10), S(O)NR^(c10)R^(d10), S(O)₂R^(b10), andS(O)₂NR^(c10)R^(b10).

In another embodiment, each R¹⁰ is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN,OR^(a10), and NR^(c10)R^(d10). In yet another embodiment, each R¹⁰ isindependently selected from C₁₋₆ alkyl, halo, and OR^(a10). In stillanother embodiment, R¹⁰ is methyl. In an embodiment, R¹⁰ is methoxy. Inanother embodiment, R¹⁰ is fluoro. In yet another embodiment, R¹⁰ ischloro.

In another embodiment, each R²⁰ is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN, OR^(a20), andNR^(c20)R^(d20); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl, areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from R²¹.

In another embodiment, each R²⁰ is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, phenyl, 5-6 membered heteroaryl, halo, D, CN,OR^(a20), and NR^(c20)R^(d20); wherein said C₁₋₆ alkyl, phenyl, and 5-6membered heteroaryl, are each optionally substituted with 1 or 2substituents independently selected from R²¹.

In another embodiment, each R²⁰ is independently selected from phenyland CN; wherein said phenyl is optionally substituted with 1 or 2substituents independently selected from R²¹.

In another embodiment, each R²¹ is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl halo, D, CN, OR^(a21), and NR^(c21)R^(d21). Inanother embodiment, each R²¹ is independently selected from halo and CN.

In an embodiment, each R³⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,D, CN, OR^(a30), SR^(a30), C(O)R^(b30), C(O)NR^(c30)R^(d30),(O)OR^(a30), C(O)R^(b30), OC(O)NR^(c30)R^(d30), NR^(c30)R^(d30),NR^(c30)C(O)R^(b30), NR³⁰C(O)OR^(a3), NR^(c30)C(O)NR^(c3)R^(d30),NR^(c30)S(O)₂R^(b30), NR^(c30)S(O)₂NR^(c30)R^(d30), S(O)₂R^(b30), andS(O)₂NR^(c30)R^(d30); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R³¹.

In another embodiment, each R³⁰ is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,halo, D, CN, OR^(a30), C(O)R^(b30), C(O)NR^(c30)R^(d30), C(O)OR^(a30),OC(O)R^(b30), OC(O)NR^(c30)R^(d30), NR^(c30)R^(d30), NR³⁰, C(O)R^(b30),and S(O)₂R^(b30); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl, are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R³¹.

In yet another embodiment, each R³⁰ is 4-10 membered heterocycloalkyloptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R³¹. In still another embodiment, each R³⁰ is 4-6 memberedheterocycloalkyl optionally substituted with 1 or 2 substituentsindependently selected from R³¹.

In another embodiment, each R³⁰ is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, D, CN, OR^(a30) and,NR^(c30)R^(d30); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl, areeach optionally substituted with 1, 2, or 3 substituents independentlyselected from R³¹.

In another embodiment, each R³⁰ is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,phenyl, 5-6 membered heteroaryl, halo, D, CN, OR^(a30) and,NR^(c30)R^(d30); wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl, and 5-6 membered heteroaryl, are eachoptionally substituted with 1 or 2 substituents independently selectedfrom R³¹.

In another embodiment, each R³⁰ is independently selected from 4-6membered heterocycloalkyl and NR^(C30)R^(d30); wherein said 4-6 memberedheterocycloalkyl is optionally 5 substituted with 1 or 2 substituentsindependently selected from R³¹.

In an embodiment, each R³¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo,D, CN, OR^(a31), SR^(a31), C(O)R^(b31), C(O)NR^(c31)R^(d31),C(O)OR^(a31), OC(O)R^(b31), OC(O)NR^(c31)R^(d31), NR^(c31)R^(d31),NR^(c31)C(O)R^(b31), NR³¹C(O)OR^(a31), NR^(c31)C(O)NR^(c31)R^(d31),NR^(c31)S(O)₂R^(b31), NR³¹S(O)₂NR^(c31)R^(d31), S(O)₂R^(b31), andS(O)₂NR^(c31)R^(d31); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl, are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R³².

In another embodiment, each R³¹ is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, D, CN,OR^(a31), and NR^(c31)R^(d31). In yet another embodiment, each R³¹ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, D, and CN. In still another embodiment, each R³¹ isC₁₋₆ alkyl. In another embodiment, R³¹ is methyl.

In another embodiment, each R⁵⁰ is independently selected from C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, D, CN, OR^(a50), C(O)R^(b50),C(O)NR^(c50)R^(d50), C(O)OR^(a50), NR^(c50)R^(d50), andNR^(c50)C(O)R^(b50). In another embodiment, each R⁵⁰ is independentlyselected from CN, OR^(a50), and C(O)NR^(c50)R^(d50).

In an embodiment, each R^(a), R^(b), R^(c), and R^(d) is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 memberedheterocycloalkyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g).

In another embodiment, each R^(a), R^(c), and R^(d) is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl, wherein C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g). In yet another embodiment, each R^(a), R^(c), andR^(d) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, and C₁₋₆ haloalkyl.

In an embodiment, each R^(a3), R^(b3), R^(c3) and R^(d3) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl, wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl, are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R³⁰. In an embodiment, each R^(a3)R^(b3),R^(c3) and R^(d3) is independently selected from H and C₁₋₆ alkyl,wherein said C₁₋₆ alkyl, is optionally substituted with 1 substituentselected from R³⁰. In an embodiment, each R^(a3), R^(b3), R^(c3) andR^(d3) is independently C₁₋₆ alkyl, wherein said C₁₋₆ alkyl, isoptionally substituted with 1 substituent selected from R³⁰. In anembodiment, each R^(a3), R^(b3), R^(c3) and R^(d3) is independently H,In an embodiment, each R^(a3), R^(b3), R^(c3) and R^(d3) isindependently C₁₋₆ alkyl,

In an embodiment, each R^(a), R^(b), R^(c6) and R^(d6) is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl. In an embodiment, each R^(a6), R^(b6), R^(c6) and R^(d6) isindependently selected from H and C₂₋₆ alkenyl. In an embodiment, eachR^(a6), R^(b6), R^(c6) and R^(d6) is independently H. In an embodiment,each R^(a6), R^(b6), R^(c6) and R^(d6) is independently C₂₋₆ alkenyl.

In an embodiment, each R^(a10), R^(b10), R^(c10), and R^(d10) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹¹.

In an embodiment, each R^(a10), R^(b10), R^(c10) and R^(d10) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl. In an embodiment, each R^(a10), R^(b10), R^(c10) andR^(d10) is independently selected from H and C₁₋₆ alkyl, In anembodiment, each R^(a10); R^(b10), R^(c10) and R^(d10) is independentlyH, In an embodiment, each R^(a10), R^(b10), R^(c10) and R^(d10) isindependently C₁₋₆ alkyl.

In an embodiment, each R^(a30), R^(c30) and R^(d30) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₁₋₆ aryl and 5-10 membered heteroaryl, are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R³¹.

In an embodiment, each R^(a30), R^(c30) and R^(d30) is independentlyselected from H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl; whereinsaid C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, phenyland 5-6 membered heteroaryl, are each optionally substituted with 1 or 2substituents independently selected from R³¹. In an embodiment, eachR^(c30) and R^(d30) is independently selected from H and C₁₋₆ alkyl.

In an embodiment, each R^(a50), R^(c50) and R^(d50), is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl. In an embodiment, eachR^(a50), R^(c50) and R^(d50) is independently selected from H and C₁₋₆alkyl.

In an embodiment, the compound of Formula I is selected from:

-   1-acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-1′,4′-dihydro-3′H-spiro-[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;-   1-acryloyl-9′-chloro-8′-(2-chloro-5-hydroxyphenyl)-7′-fluoro-1′,4′-dihydro-3′H-spiro-[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;-   1-acryloyl-9′-chloro-7′-fluoro-8′-(3-methyl-1H-indazol-4-yl)-1′,4′-dihydro-3′H-spiro-[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;-   1-acryloyl-9′-chloro-7′-fluoro-8′-(5-methyl-1H-indazol-4-yl)-1′,4′-dihydro-3′H-spiro-[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;-   1-acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-methoxyphenyl)-1′,4′-dihydro-3′H-spiro-[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;-   1-acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-1′,4′-dihydro-3′H-spiro-[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one;-   1-acryloyl-9′-chloro-7′-fluoro-8′-(5-methyl-1H-indazol-4-yl)-1′,4′-dihydro-3′H-spiro-[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one;-   1′-acryloyl-9-chloro-7-fluoro-8-(2-fluoro-6-hydroxyphenyl)-1,4-dihydro-3H-spiro-[pyrazino[2,3-c]quinoline-2,3′-pyrrolidin]-3-one;-   1′-acryloyl-9-chloro-7-fluoro-8-(5-methyl-1H-indazol-4-yl)-1,4-dihydro-3H-spiro-[pyrazino[2,3-c]quinoline-2,3′-pyrrolidin]-3-one;-   1-acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-5′-((1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;-   1-acryloyl-9′-chloro-7′-fluoro-8′-(3-hydroxynaphthalen-1-yl)-5′-((1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;-   1-acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-5′-(2-(piperidin-1-yl)ethoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;-   1-acryloyl-8′-chloro-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-((1-methylpyrrolidin-2-yl)methoxy)spiro[piperidine-4,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one;-   1-acryloyl-8′-chloro-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-((1-methylpyrrolidin-2-yl)methoxy)spiro[pyrrolidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one;-   1-acryloyl-8′-chloro-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-3′-methyl-4′-((1-methyl-pyrrolidin-2-yl)methoxy)spiro[piperidine-4,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one;-   1-acryloyl-9′-chloro-7′-fluoro-8′-(3-hydroxynaphthalen-1-yl)spiro[piperidine-4,2′-pyrano-[3,2-c]quinolin]-4′(3′H)-one;    and-   1-acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-5′-((1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one;    -   or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound of Formula I is selected from:

-   4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-8′-methylspiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one;-   8′-chloro-7′-(7-chloro-3-hydroxynaphthalen-1-yl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluorospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one;-   8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-pyrrolo[2,3-c]quinolin]-2′(3′)-one;-   3-amino-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)spiro[cyclobutane-1,1′-pyrrolo[2,3-c]quinolin]-2′(3′)-one;-   4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;-   2-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)acetonitrile;-   3-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)propanenitrile;-   8′-(2-chlorobenzyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)spiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′)-one;-   2-((4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)methyl)benzonitrile;-   4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile-   3-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[azetidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)propanenitrile;-   4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[pyrrolidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;-   4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[morpholine-2,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;-   4-(6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;-   4-(6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-3′-methyl-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;-   4-(6′-fluoro-3′-(2-hydroxyethyl)-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;-   4-(6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-3′-isopentyl-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;-   4-(3′-(cyanomethyl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;    and-   2-(8′-(3-cyanopropyl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-3′(2′H)-yl)acetamide;    -   or a pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a pharmaceutical compositioncomprising the compound of Formula I, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.

In an aspect, provided herein is a method of inhibiting a KRAS proteinharboring a G12C mutation, said method comprising contacting a compoundof the instant disclosure with KRAS.

In another aspect, provided herein is a method of inhibiting a KRASprotein harboring a G12D mutation, said method comprising contacting acompound of the instant disclosure with KRAS.

In yet another aspect, provided herein is a method of inhibiting a KRASprotein harboring a G12V mutation, said method comprising contacting acompound of the instant disclosure with KRAS.

In an embodiment, compounds of the Formulae herein are compounds of theFormulae or pharmaceutically acceptable salts thereof.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds ofFormula I can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)— includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or aryene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted,” unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C_(n-m) alkyl,” refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene,” employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, ethan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl,propan-1,1-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl,2-methyl-propan-1,3-diyl and the like.

The term “alkoxy,” employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms. The term “C_(n-m) dialkoxy” refers to a linking groupof formula —O—(C_(n-m) alkyl)-O—, the alkyl group of which has n to mcarbons. Example dialkyoxy groups include —OCH₂CH₂O— and OCH₂CH₂CH₂—. Insome embodiments, the two O atoms of a C_(n-m) dialkoxy group may beattached to the same B atom to form a 5- or 6-membered heterocycloalkylgroup.

The term “alkylthio,” employed alone or in combination with other terms,refers to a group of formula —S-alkyl, wherein the alkyl group is asdefined above.

The term “amino,” employed alone or in combination with other terms,refers to a group of formula —NH₂, wherein the hydrogen atoms may besubstituted with a substituent described herein. For example,“alkylamino” can refer to —NH(alkyl) and —N(alkyl)₂.

The term “carbonyl,” employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C≡N, whichalso may be written as —CN.

The term “carbamyl,” as used herein, refers to a —NHC(O)O— or —OC(O)NH—group, wherein the carbon atom is doubly bound to one oxygen atom, andsingly bound to a nitrogen and second oxygen atom.

The term “sulfonyl” refers to a —SO₂— group wherein a sulfur atom isdoubly bound to two oxygen atoms.

The terms “halo” or “halogen,” used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C_(n-m) alkyl group having n tom carbon atoms and from at least one up to {2(n to m)+1}halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments,the haloalkyl group is a fluoroalkyl group.

The term “haloalkoxy,” employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” or “oxy” refers to an oxygen atom as a divalentsubstituent, forming a carbonyl group when attached to carbon, orattached to a heteroatom forming a sulfoxide or sulfone group, or anN-oxide group. In some embodiments, heterocyclic groups may beoptionally substituted by 1 or 2 oxo (═O) substituents.

The term “oxidized” in reference to a ring-forming N atom refers to aring-forming N-oxide.

The term “oxidized” in reference to a ring-forming S atom refers to aring-forming sulfonyl or ring-forming sulfinyl.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, and the like. In some embodiments, arylgroups have from 6 to about 10 carbon atoms. In some embodiments arylgroups have 6 carbon atoms. In some embodiments aryl groups have 10carbon atoms. In some embodiments, the aryl group is phenyl. In someembodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-10 ring atomsincluding carbon atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl,thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-,1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine),indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl,imidazo[1,2-b]thiazolyl, purinyl, and the like. In some embodiments, theheteroaryl group is pyridone (e.g., 2-pyridone).

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from nitrogen, sulfur, oxygen and phosphorus, and which has4-10 ring members, 4-7 ring members, or 4-6 ring members. Includedwithin the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and7-membered heterocycloalkyl groups.

Heterocycloalkyl groups can include mono- or bicyclic (e.g., having twofused or bridged rings) or spirocyclic ring systems. In someembodiments, the heterocycloalkyl group is a monocyclic group having 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur andoxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkylgroup can be optionally oxidized to form an oxo or sulfido group orother oxidized linkage (e.g., C(O), S(O), C(S) or S(O)₂, N-oxide etc.)or a nitrogen atom can be quaternized. The heterocycloalkyl group can beattached through a ring-forming carbon atom or a ring-formingheteroatom. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 double bonds. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the heterocycloalkyl ring, e.g.,benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. Examples of heterocycloalkyl groups include2,5-diazobicyclo[2.2.1]heptanyl; pyrrolidinyl;hexahydropyrrolo[3,4-b]pyrrol-1(2)-yl; 1,6-dihydropyridinyl;morpholinyl; azetidinyl; piperazinyl; and 4,7-diazaspiro[2.5]octan-7-yl.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as β-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of α-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art (Deuterium Labeling in OrganicChemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts,1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau,Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007,7744-7765; The Organic Chemistry of Isotopic Labelling by James R.Hanson, Royal Society of Chemistry, 2011). Isotopically labeledcompounds can used in various studies such as NMR spectroscopy,metabolism experiments, and/or assays.

Substitution with heavier isotopes such as deuterium, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. (A. Kerekes et. al. J.Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm.2015, 58, 308-312).

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J.Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high-performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of formula 1-12 can be prepared via the synthetic routeoutlined in Scheme 1. Halogenation of starting material 1-1 with anappropriate reagent, such as N-chloro-succinimide (NCS), first affordsintermediate 1-2 (Hal is a halide, such as F, Cl, Br, or I). Compound1-4 can then be prepared by a condensation reaction of 1-2 with2,2-dimethyl-1,3-dioxane-4,6-dione (1-3) and triethoxymethane, followedby decarboxylation under thermal condition. Nitration of intermediate1-4 with nitric acid gives the nitro adduct 1-5, which upon treatmentwith a reagent, such as POCl₃, yields intermediate 1-6. A S_(N)Arreaction of 1-6 with an amine adduct of formula 1-7 (PG is anappropriate protecting group, such as Boc) then generate compound 1-8.The nitro functionality in 1-8 is reduced under suitable conditions(such as using Fe in acetic acid), followed by a cyclization reaction,to deliver product 1-9. Removal of the protecting group (PG) in 1-9,followed by functionalization of the resulting amine adduct (e.g.reacting with acryloyl chloride), generates intermediate 1-10. Thedesired product 1-12 can then be prepared by a coupling reaction ofcompound 1-10 with an adduct of formula 1-11, in which M is a boronicacid, boronic ester or an appropriately substituted metal [e.g., M isB(OR)₂, Sn(Alkyl)₃, or Zn-Hal], under standard Suzuki Cross-Couplingconditions (Tetrahedron 2002, 58, 9633-9695) (e.g., in the presence of apalladium catalyst and a suitable base), or standard Stillecross-coupling conditions (ACS Catalysis 2015, 5, 3040-3053) (e.g., inthe presence of a palladium catalyst), or standard Negishicross-coupling conditions (ACS Catalysis 2016, 6, 1540-1552) (e.g., inthe presence of a palladium catalyst). The order of the above describedchemical reactions can be rearranged as appropriate to suit thepreparation of different analogues.

Compounds of formula 2-13 can be prepared via the synthetic routeoutlined in Scheme 2. Halogenation of starting material 2-1 with anappropriate reagent, such as N-chloro-succinimide (NCS), first affordsintermediate 2-2 (Hal is a halide, such as F, Cl, Br, or I). Compound2-3 can then be prepared by treatment of intermediate 2-2 with anappropriate reagent, such as triphosgene. Further condensation reactionof 2-3 with reagent 2-4 delivers nitro compound 2-5, which was treatedwith POCl₃ to yield intermediate 2-6. A S_(N)Ar reaction of 2-6 with anamine adduct of formula 2-7 (PG is an appropriate protecting group, suchas Boc) then generate compound 2-8. The R⁴ group in 2-9 can then beinstalled via a suitable transformation, such as a S_(N)Ar reaction or acoupling reaction. The nitro functionality in 2-9 is reduced undersuitable conditions (such as using Fe in acetic acid), followed by acyclization reaction, to deliver product 2-10. Removal of the protectinggroup (PG) in 2-10, followed by functionalization of the resulting amineadduct (e.g. reacting with acryloyl chloride), generates intermediate2-11. The desired product 2-13 can then be prepared by a couplingreaction of compound 2-11 with an adduct of formula 2-12, in which M isa boronic acid, boronic ester or an appropriately substituted metal[e.g., M is B(OR)₂, Sn(Alkyl)₃, or Zn-Hal], under standard SuzukiCross-Coupling conditions (e.g., in the presence of a palladium catalystand a suitable base), or standard Stille cross-coupling conditions(e.g., in the presence of a palladium catalyst), or standard Negishicross-coupling conditions (e.g., in the presence of a palladiumcatalyst). The order of the above described chemical reactions can berearranged as appropriate to suit the preparation of differentanalogues.

Compounds of formula 3-9 can be prepared via the synthetic routeoutlined in Scheme 3. A S_(N)Ar reaction of starting material 3-1(prepared following procedures described in Scheme 2) with an adduct offormula 3-2, in the presence of an appropriate base (e.g. KHMDS), firstaffords compound 3-3. The R⁴ group in 3-4 can then be installed via asuitable transformation, such as a S_(N)Ar reaction or a couplingreaction. The nitro functionality in 3-4 is reduced under suitableconditions (such as using Fe in acetic acid), followed by a cyclizationreaction, to deliver product 3-5. Intermediate 3-5 can then befunctionalized (e.g. an alkylation reaction) into compound 3-6. Removalof the protecting group (PG) in 3-6, followed by functionalization ofthe resulting amine adduct (e.g. reacting with acryloyl chloride),generates intermediate 3-7. The desired product 3-9 can then be preparedby a coupling reaction of compound 3-7 with an adduct of formula 3-8, inwhich M is a boronic acid, boronic ester or an appropriately substitutedmetal [e.g., M is B(OR)₂, Sn(Alkyl)₃, or Zn-Hal], under standard SuzukiCross-Coupling conditions (e.g., in the presence of a palladium catalystand a suitable base), or standard Stille cross-coupling conditions(e.g., in the presence of a palladium catalyst), or standard Negishicross-coupling conditions (e.g., in the presence of a palladiumcatalyst). The order of the above described chemical reactions can berearranged or omitted as appropriate to suit the preparation ofdifferent analogues.

Compounds of formula 4-9 can be prepared via the synthetic routeoutlined in Scheme 4. Halogenation of starting material 4-1 with anappropriate reagent, such as N-chloro-succinimide (NCS), first affordsintermediate 4-2 (Hal is a halide, such as F, Cl, Br, or I).Intermediate 4-4 can then be prepared by a condensation reaction ofintermediate 4-2 with ethyl 3-oxobutanoate (4-3) and triethylorthoformate, followed by decarboxylation under thermal condition.Treatment of intermediate 4-4 with ketone 4-5, in the presence of asuitable base (e.g. pyrrolidine), generates compound 4-6. Removal of theprotecting group (PG) in 4-6, followed by functionalization of theresulting amine adduct (e.g. reacting with acryloyl chloride), yieldsintermediate 4-7. Product 4-9 can then be prepared by coupling of 4-7with an adduct of formula 4-8, in which M is a boronic acid, boronicester or an appropriately substituted metal [e.g., M is B(OR)₂,Sn(Alkyl)₃, or Zn-Hal], under standard Suzuki Cross-Coupling conditions(e.g., in the presence of a palladium catalyst and a suitable base), orstandard Stille cross-coupling conditions (e.g., in the presence of apalladium catalyst), or standard Negishi cross-coupling conditions(e.g., in the presence of a pallidum catalyst). The order of the abovedescribed chemical reactions can be rearranged as appropriate to suitthe preparation of different analogues.

Compounds of formula 5-6 can be prepared via the synthetic routeoutlined in Scheme 5. Starting material 5-1 (prepared followingprocedures described in Scheme 3) can be functionalized (e.g. a Negishicross-coupling reaction) into compound 5-2. Intermediate 5-4 can beprepared by a coupling reaction of compound 5-2 with an adduct offormula 5-3, in which M is a boronic acid, boronic ester or anappropriately substituted metal [e.g., M is B(OR)₂, Sn(Alkyl)₃, orZn-Hal], under standard Suzuki Cross-Coupling conditions (e.g., in thepresence of a palladium catalyst and a suitable base), or standardStille cross-coupling conditions (e.g., in the presence of a palladiumcatalyst), or standard Negishi cross-coupling conditions (e.g., in thepresence of a palladium catalyst). Intermediate 5-4 can then befunctionalized (e.g. an alkylation reaction) into compound 5-5. Thedesired product 5-6 can then be prepared by removing the protectinggroup (PG) in 5-5. The order of the above described chemical reactionscan be rearranged or omitted as appropriate to suit the preparation ofdifferent analogues.

Compounds of formula 6-7 can be prepared via the synthetic routeoutlined in Scheme 6. The lactam functionality in the starting material6-1 (prepared following procedures described in Scheme 5) can beprotected to afford compound 6-2. The carbonyl in the protected lactamcompound 6-2 can be functionalized by a nucleophilic addition reactionto give intermediate 6-3. Removal of the protecting group (PG′) in 6-3,followed by an elimination reaction generates intermediate 6-4.Reduction of 6-4 under suitable conditions delivers compound 6-5.Compound 6-5 can then be functionalized (e.g. an alkylation reaction)into compound 6-6. The desired product 6-7 can then be prepared byremoving the protecting group (PG) in 6-6. The order of the abovedescribed chemical reactions can be rearranged or omitted as appropriateto suit the preparation of different analogues.

KRAS Protein

The Ras family is comprised of three members; KRAS, NRAS and HRAS. RASmutant cancers account for about 25% of human cancers. KRAS is the mostfrequently mutated isoform in human cancers: 85% of all RAS mutationsare in KRAS, 12% in NRAS, and 3% in HRAS (Simanshu, D. et al. Cell 170.1(2017):17-33). KRAS mutations are prevalent amongst the top three mostdeadly cancer types: pancreatic (97%), colorectal (44%), and lung (30%)(Cox, A. D. et al. Nat Rev Drug Discov (2014) 13:828-51). The majorityof RAS mutations occur at amino acid residues/codons 12, 13, and 61;Codon 12 mutations are most frequent in KRAS. The frequency of specificmutations varied between RAS genes and G12D mutations are mostpredominant in KRAS whereas Q61R and G12R mutations are most frequent inNRAS and HRAS. Furthermore, the spectrum of mutations in a RAS isoformdiffers between cancer types. For example, KRAS G12D mutationspredominate in pancreatic cancers (51%), followed by colorectaladenocarcinomas (45%) and lung cancers (17%) (Cox, A. D. et al. Nat RevDrug Discov (2014) 13:828-51). In contrast, KRAS G12C mutationspredominate in non-small cell lung cancer (NSCLC) comprising 11-16% oflung adenocarcinomas (nearly half of mutant KRAS is G12C), as well as2-5% of pancreatic and colorectal adenocarcinomas, respectively (Cox, A.D. et al. Nat Rev Drug Discov (2014) 13:828-51). Genomic studies usingshRNA knockdown thousands of genes across hundreds of cancer cell lineshave demonstrated that cancer cells exhibiting KRAS mutations are highlydependent on KRAS function for cell growth (McDonald, R. et al. Cell 170(2017): 577-592). Taken together, these findings suggested that KRASmutations play a critical role in human cancers, therefore developmentof the inhibitors targeting mutant KRAS may be useful in the clinicaltreatment of diseases that have characterized by a KRAS mutation.

Methods of Use

The cancer types in which KRAS harboring G12C, G12V, and G12D mutationsare implicated include, but are not limited to: carcinomas (e.g.,pancreatic, colorectal, lung, bladder, gastric, esophageal, breast, headand neck, cervical skin, thyroid); hematopoietic malignancies (e.g.,myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS),chronic and juvenile myelomonocytic leukemia (CMML and JMML), acutemyeloid leukemia (AML), acute lymphocytic leukemia (ALL) and multiplemyeloma (MM)); and other neoplasms (e.g., glioblastoma and sarcomas). Inaddition, KRAS mutations were found in acquired resistance to anti-EGFRtherapy (Knickelbein, K. et al. Genes & Cancer, (2015): 4-12). KRASmutations were found in immunological and inflammatory disorders(Fernandez-Medarde, A. et al. Genes & Cancer, (2011): 344-358) such asRas-associated lymphoproliferative disorder (RALD) or juvenilemyelomonocytic leukemia (JMML) caused by somatic mutations of KRAS orNRAS.

Compounds of the present disclosure can inhibit the activity of KRAS.For example, compounds of the present disclosure can be used to inhibitactivity of KRAS in a cell or in an individual or patient in need ofinhibition of the enzyme by administering an inhibiting amount of one ormore compounds of the present disclosure to the cell, individual, orpatient.

In an aspect, provided herein is a method of inhibiting KRAS activity,said method comprising administering to a patient in need thereof atherapeutically effective amount of a compound of any of the formulaedisclosed herein.

In another aspect, provided herein is a method of treating aKRAS-mediated disease or disorder in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of the compound of any of the formulae disclosed herein.

In an embodiment, the disease or disorder is an immunological orinflammatory disorder.

In another embodiment, the immunological or inflammatory disorder isRas-associated lymphoproliferative disorder and juvenile myelomonocyticleukemia caused by somatic mutations of KRAS.

In an aspect, provided herein is a method of treating a disease ordisorder associated with inhibiting a KRAS protein harboring a G12Cmutation, said method comprising administering to a patient in needthereof a therapeutically effective amount of a compound of any of theformulae disclosed herein, or pharmaceutically acceptable salt thereof.

In another aspect, provided herein is a method of treating cancer in asubject in need thereof comprising administering to the subject atherapeutically effective amount of the compound of any of the formulaedisclosed herein.

In an embodiment, the cancer is selected from carcinomas, hematologicalcancers, sarcomas, and glioblastoma.

In another embodiment, the hematological cancer is selected frommyeloproliferative neoplasms, myelodysplastic syndrome, chronic andjuvenile myelomonocytic leukemia, acute myeloid leukemia, acutelymphocytic leukemia, and multiple myeloma.

In yet another embodiment, the carcinoma is selected from pancreatic,colorectal, lung, bladder, gastric, esophageal, breast, head and neck,cervical, skin, and thyroid.

In still another aspect, provided herein is a method of treating adisease or disorder associated with inhibiting a KRAS protein harboringa G12C mutation, said method comprising administering to a patient inneed thereof a therapeutically effective amount of the compound of anyof the formulae disclosed herein, or a pharmaceutically acceptable saltthereof.

In another aspect, provided herein is a method of treating cancer in apatient in need thereof comprising administering to the patient atherapeutically effective amount of the compounds disclosed hereinwherein the cancer is characterized by an interaction with a KRASprotein harboring a G12C mutation.

In another aspect, provided herein is a method for treating a disease ordisorder associated with inhibition of KRAS interaction or a mutantthereof in a patient in need thereof comprising the step ofadministering to the patient a compound disclosed herein, or apharmaceutically acceptable salt thereof, or a composition comprising acompound disclosed herein or a pharmaceutically acceptable salt thereof,in combination with another therapy or therapeutic agent as describedherein.

In some embodiments, the compounds of the disclosure have selectiveinhibitory activity for KRAS over other RAS proteins. In someembodiments, the selectivity of the compounds of the disclosure for KRASover other RAS proteins is 10-fold to 25-fold, or 25-fold to 50-fold.

As KRAS inhibitors, the compounds of the present disclosure are usefulin the treatment of various diseases associated with abnormal expressionor activity of KRAS. Compounds that inhibit KRAS will be useful inproviding a means of preventing the growth or inducing apoptosis intumors, particularly by inhibiting angiogenesis. It is thereforeanticipated that compounds of the present disclosure will prove usefulin treating or preventing proliferative disorders such as cancers. Inparticular, tumors with activating mutants of receptor tyrosine kinasesor upregulation of receptor tyrosine kinases may be particularlysensitive to the inhibitors.

In certain embodiments, the disclosure provides a method for treating aKRAS-mediated disorder in a subject in need thereof, comprising the stepof administering to said patient a compound according to the invention,or a pharmaceutically acceptable composition thereof.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET), myelodysplasiasyndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiplemyeloma, cutaneous T-cell lymphoma, adult T-cell leukemia, Waldenstrom'sMacroglubulinemia, hairy cell lymphoma, marginal zone lymphoma, chronicmyelogenic lymphoma and Burkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma,lymphosarcoma, leiomyosarcoma, and teratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, mesothelioma, pavicellular and non-pavicellularcarcinoma, bronchial adenoma and pleuropulmonary blastoma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (exocrinepancreatic carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma,gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma,lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma,lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubularadenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer, gallbladder cancer and anal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma),bladder and urethra (squamous cell carcinoma, transitional cellcarcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis(seminoma, teratoma, embryonal carcinoma, teratocarcinoma,choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma,fibroadenoma, adenomatoid tumors, lipoma) and urothelial carcinoma.

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors, neuro-ectodermal tumors), and spinal cord(neurofibroma, meningioma, glioma, sarcoma), neuroblastoma,Lhermitte-Duclos disease and pineal tumors.

Exemplary gynecological cancers include cancers of the breast (ductalcarcinoma, lobular carcinoma, breast sarcoma, triple-negative breastcancer, HER2-positive breast cancer, inflammatory breast cancer,papillary carcinoma), uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma(serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers, tumors ofthe eye, tumors of the lips and mouth and squamous head and neck cancer.

The compounds of the present disclosure can also be useful in theinhibition of tumor metastases.

In addition to oncogenic neoplasms, the compounds of the invention areuseful in the treatment of skeletal and chondrocyte disorders including,but not limited to, achrondroplasia, hypochondroplasia, dwarfism,thanatophoric dysplasia (TD) (clinical forms TD I and TD II), Apertsyndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevensoncutis gyrate syndrome, Pfeiffer syndrome, and craniosynostosissyndromes. In some embodiments, the present disclosure provides a methodfor treating a patient suffering from a skeletal and chondrocytedisorder.

In some embodiments, compounds described herein can be used to treatAlzheimer's disease, HIV, or tuberculosis.

As used herein, the term “8p11 myeloproliferative syndrome” is meant torefer to myeloid/lymphoid neoplasms associated with eosinophilia andabnormalities of FGFR1.

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture. Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the KRAS enzyme with a compound described hereinincludes the administration of a compound described herein to anindividual or patient, such as a human, having KRAS, as well as, forexample, introducing a compound described herein into a samplecontaining a cellular or purified preparation containing the KRASprotein.

As used herein, the term “individual,” “subject,” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent such as an amountof any of the solid forms or salts thereof as disclosed herein thatelicits the biological or medicinal response in a tissue, system,animal, individual or human that is being sought by a researcher,veterinarian, medical doctor or other clinician. An appropriate“effective” amount in any individual case may be determined usingtechniques known to a person skilled in the art.

The phrase “pharmaceutically acceptable” is used herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, immunogenicity or other problem orcomplication, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase “pharmaceutically acceptable carrier orexcipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. Excipients or carriers are generallysafe, non-toxic and neither biologically nor otherwise undesirable andinclude excipients or carriers that are acceptable for veterinary use aswell as human pharmaceutical use. In one embodiment, each component is“pharmaceutically acceptable” as defined herein. See, e.g., Remington:The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the AmericanPharmaceutical Association: 2009; Handbook of Pharmaceutical Additives,3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., 2009.

As used herein, the term “treating” or “treatment” refers to inhibitinga disease; for example, inhibiting a disease, condition, or disorder inan individual who is experiencing or displaying the pathology orsymptomology of the disease, condition, or disorder (i.e., arrestingfurther development of the pathology and/or symptomology) orameliorating the disease; for example, ameliorating a disease,condition, or disorder in an individual who is experiencing ordisplaying the pathology or symptomology of the disease, condition, ordisorder (i.e., reversing the pathology and/or symptomology) such asdecreasing the severity of the disease.

The term “prevent,” “preventing,” or “prevention” as used herein,comprises the prevention of at least one symptom associated with orcaused by the state, disease or disorder being prevented.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment (while the embodimentsare intended to be combined as if written in multiply dependent form).Conversely, various features of the invention which are, for brevity,described in the context of a single embodiment, can also be providedseparately or in any suitable subcombination.

Combination Therapy

One or more additional pharmaceutical agents or treatment methods suchas, for example, anti-viral agents, chemotherapeutics or otheranti-cancer agents, immune enhancers, immunosuppressants, radiation,anti-tumor and anti-viral vaccines, cytokine therapy (e.g., IL2, GM-CSF,etc.), and/or tyrosine kinase inhibitors can be used in combination withcompounds described herein for treatment of KRAS-associated diseases,disorders or conditions, or diseases or conditions as described herein.The agents can be combined with the present compounds in a single dosageform, or the agents can be administered simultaneously or sequentiallyas separate dosage forms.

Compounds described herein can be used in combination with one or moreother kinase inhibitors for the treatment of diseases, such as cancer,that are impacted by multiple signaling pathways. For example, acombination can include one or more inhibitors of the following kinasesfor the treatment of cancer: Akt1, Akt2, Akt3, TGF-pRβ, Pim, PKA, PKG,PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR,HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT,FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron,Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Ft2, Flt4, EphA1, EphA2, EphA3,EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL,ALK and B-Raf. Additionally, the solid forms of the KRAS inhibitor asdescribed herein can be combined with inhibitors of kinases associatedwith the PIK3/Akt/mTOR signaling pathway, such as PI3K, Akt (includingAkt1, Akt2 and Akt3) and mTOR kinases.

In some embodiments, compounds described herein can be used incombination with one or more inhibitors of the enzyme or proteinreceptors such as HPK1, SBLB, TUT4, A2A/A2B, CD47, CDK2, STING, ALK2,LIN28, ADAR1, MAT2a, RIOK1, HDAC8, WDR5, SMARCA2, and DCLK1 for thetreatment of diseases and disorders. Exemplary diseases and disordersinclude cancer, infection, inflammation and neurodegenerative disorders.

In some embodiments, compounds described herein can be used incombination with a therapeutic agent that targets an epigeneticregulator. Examples of epigenetic regulators include bromodomaininhibitors, the histone lysine methyltransferases, histone argininemethyl transferases, histone demethylases, histone deacetylases, histoneacetylases, and DNA methyltransferases. Histone deacetylase inhibitorsinclude, e.g., vorinostat. For treating cancer and other proliferativediseases, compounds described herein can be used in combination withtargeted therapies, including JAK kinase inhibitors (Ruxolitinib,additional JAK1/2 and JAK1-selective, baricitinib or INCB39110), Pimkinase inhibitors (e.g., LGH447, INCB053914 and SGI-1776), PI3 kinaseinhibitors including PI3K-delta selective and broad spectrum PI3Kinhibitors (e.g., INCB50465 and INCB54707), PI3K-gamma inhibitors suchas PI3K-gamma selective inhibitors, MEK inhibitors, CSF1R inhibitors(e.g., PLX3397 and LY3022855), TAM receptor tyrosine kinases inhibitors(Tyro-3, Axl, and Mer; e.g., INCB81776), angiogenesis inhibitors,interleukin receptor inhibitors, Cyclin Dependent kinase inhibitors,BRAF inhibitors, mTOR inhibitors, proteasome inhibitors (Bortezomib,Carfilzomib), HDAC-inhibitors (panobinostat, vorinostat), DNA methyltransferase inhibitors, dexamethasone, bromo and extra terminal familymembers inhibitors (for example, bromodomain inhibitors or BETinhibitors, such as OTX015, CPI-0610, INCB54329 or INCB57643), LSD1inhibitors (e.g., GSK2979552, INCB59872 and INCB60003), arginaseinhibitors (e.g., INCB1158), indoleamine 2,3-dioxygenase inhibitors(e.g., epacadostat, NLG919 or BMS-986205), PARP inhibitors (e.g.,olaparib or rucaparib), and inhibitors of BTK such as ibrutinib.

In addition, for treating cancer and other proliferative diseases,compounds described herein can be used in combination with targetedtherapies such as, e.g., c-MET inhibitors (e.g., capmatinib), ananti-CD19 antibody (e.g., tafasitamab), an ALK2 inhibitor (e.g.,INCB00928); or combinations thereof.

For treating cancer and other proliferative diseases, compoundsdescribed herein can be used in combination with chemotherapeuticagents, agonists or antagonists of nuclear receptors, or otheranti-proliferative agents. Compounds described herein can also be usedin combination with a medical therapy such as surgery or radiotherapy,e.g., gamma-radiation, neutron beam radiotherapy, electron beamradiotherapy, proton therapy, brachytherapy, and systemic radioactiveisotopes.

Examples of suitable chemotherapeutic agents include any of: abarelix,abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, amidox, amsacrine, anastrozole,aphidicolon, arsenic trioxide, asparaginase, axitinib, azacitidine,bevacizumab, bexarotene, baricitinib, bendamustine, bicalutamide,bleomycin, bortezombi, bortezomib, brivanib, buparlisib, busulfanintravenous, busulfan oral, calusterone, camptosar, capecitabine,carboplatin, carmustine, cediranib, cetuximab, chlorambucil, cisplatin,cladribine, clofarabine, crizotinib, cyclophosphamide, cytarabine,dacarbazine, dacomitinib, dactinomycin, dalteparin sodium, dasatinib,dactinomycin, daunorubicin, decitabine, degarelix, denileukin,denileukin diftitox, deoxycoformycin, dexrazoxane, didox, docetaxel,doxorubicin, droloxafine, dromostanolone propionate, eculizumab,enzalutamide, epidophyllotoxin, epirubicin, epothilones, erlotinib,estramustine, etoposide phosphate, etoposide, exemestane, fentanylcitrate, filgrastim, floxuridine, fludarabine, fluorouracil, flutamide,fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelinacetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lonafarnib, lomustine, meclorethamine,megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, niraparib, nofetumomab, oserelin, oxaliplatin,paclitaxel, pamidronate, panitumumab, panobinostat, pazopanib,pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin,pilaralisib, pipobroman, plicamycin, ponatinib, porfimer, prednisone,procarbazine, quinacrine, ranibizumab, rasburicase, regorafenib,reloxafine, revlimid, rituximab, rucaparib, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur,temozolomide, teniposide, testolactone, tezacitabine, thalidomide,thioguanine, thiotepa, tipifarnib, topotecan, toremifene, tositumomab,trastuzumab, tretinoin, triapine, trimidox, triptorelin, uracil mustard,valrubicin, vandetanib, vinblastine, vincristine, vindesine,vinorelbine, vorinostat, veliparib, talazoparib, and zoledronate.

In some embodiments, compounds described herein can be used incombination with immune checkpoint inhibitors. Exemplary immunecheckpoint inhibitors include inhibitors against immune checkpointmolecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR,CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3 (e.g., INCAGN2385),TIM3 (e.g., INCB2390), VISTA, PD-1, PD-L1 and PD-L2. In someembodiments, the immune checkpoint molecule is a stimulatory checkpointmolecule selected from CD27, CD28, CD40, ICOS, OX40 (e.g., INCAGN1949),GITR (e.g., INCAGN1876) and CD137. In some embodiments, the immunecheckpoint molecule is an inhibitory checkpoint molecule selected fromA2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA.In some embodiments, the compounds provided herein can be used incombination with one or more agents selected from KIR inhibitors, TIGITinhibitors, LAIR¹ inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRbeta inhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule is asmall molecule PD-L1 inhibitor. In some embodiments, the small moleculePD-L1 inhibitor has an IC50 less than 1 μM, less than 100 nM, less than10 nM or less than 1 nM in a PD-L1 assay described in US PatentPublication Nos. US 20170107216, US 20170145025, US 20170174671,US20170174679, US20170320875, US20170342060, US20170362253, and US20180016260, each of which is incorporated by reference in its entiretyfor all purposes.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is MGA012 (retifanlimab),nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210,PDR001, ipilumimab orAMP-224. In some embodiments, the anti-PD-1monoclonal antibody is nivolumab or pembrolizumab. In some embodiments,the anti-PD1 antibody is pembrolizumab. In some embodiments, theanti-PD1 antibody is nivolumab. In some embodiments, the anti-PD-1monoclonal antibody is MGA012 (retifanlimab). In some embodiments, theanti-PD1 antibody is SHR-1210. Other anti-cancer agent(s) includeantibody therapeutics such as 4-1BB (e.g. urelumab, utomilumab.

In some embodiments, the compounds of the disclosure can be used incombination with INCB086550.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab, tremelimumab,AGEN1884, or CP-675,206.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, or INCAGN2385.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is INCAGN2390, MBG453, or TSR-022.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, INCAGN1876, MK-1248, AMG228,BMS-986156, GWN323, or MED11873.

In some embodiments, the inhibitor of an immune checkpoint molecule isan agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.In some embodiments, the anti-OX40 antibody is MED10562, MOXR-0916,PF-04518600, GSK3174998, or BMS-986178. In some embodiments, the OX40Lfusion protein is MED16383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

In some embodiments, the compounds of the disclosure can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat,NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.

In some embodiments, the compounds described herein can be used incombination with one or more agents for the treatment of diseases suchas cancer. In some embodiments, the agent is an alkylating agent, aproteasome inhibitor, a corticosteroid, or an immunomodulatory agent.Examples of an alkylating agent include cyclophosphamide (CY), melphalan(MEL), and bendamustine. In some embodiments, the proteasome inhibitoris carfilzomib. In some embodiments, the corticosteroid is dexamethasone(DEX). In some embodiments, the immunomodulatory agent is lenalidomide(LEN) or pomalidomide (POM).

Suitable antiviral agents contemplated for use in combination withcompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6-diamino-purine dioxolane); and Iodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

Suitable agents for use in combination with compounds described hereinfor the treatment of cancer include chemotherapeutic agents, targetedcancer therapies, immunotherapies or radiation therapy. Compoundsdescribed herein may be effective in combination with anti-hormonalagents for treatment of breast cancer and other tumors. Suitableexamples are anti-estrogen agents including but not limited to tamoxifenand toremifene, aromatase inhibitors including but not limited toletrozole, anastrozole, and exemestane, adrenocorticosteroids (e.g.prednisone), progestins (e.g. megastrol acetate), and estrogen receptorantagonists (e.g. fulvestrant). Suitable anti-hormone agents used fortreatment of prostate and other cancers may also be combined withcompounds described herein. These include anti-androgens including butnot limited to flutamide, bicalutamide, and nilutamide, luteinizinghormone-releasing hormone (LHRH) analogs including leuprolide,goserelin, triptorelin, and histrelin, LHRH antagonists (e.g.degarelix), androgen receptor blockers (e.g. enzalutamide) and agentsthat inhibit androgen production (e.g. abiraterone).

The compounds described herein may be combined with or in sequence withother agents against membrane receptor kinases especially for patientswho have developed primary or acquired resistance to the targetedtherapy. These therapeutic agents include inhibitors or antibodiesagainst EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 and againstcancer-associated fusion protein kinases such as Bcr-Abl and EML4-Ak.Inhibitors against EGFR include gefitinib and erlotinib, and inhibitorsagainst EGFR/Her2 include but are not limited to dacomitinib, afatinib,lapitinib and neratinib. Antibodies against the EGFR include but are notlimited to cetuximab, panitumumab and necitumumab. Inhibitors of c-Metmay be used in combination with KRAS inhibitors. These includeonartumzumab, tivantnib, and INC-280. Agents against Ab (or Bcr-Abl)include imatinib, dasatinib, nilotinib, and ponatinib and those againstAlk (or EML4-ALK) include crizotinib.

Angiogenesis inhibitors may be efficacious in some tumors in combinationwith KRAS inhibitors. These include antibodies against VEGF or VEGFR orkinase inhibitors of VEGFR. Antibodies or other therapeutic proteinsagainst VEGF include bevacizumab and aflibercept. Inhibitors of VEGFRkinases and other anti-angiogenesis inhibitors include but are notlimited to sunitinib, sorafenib, axitinib, cediranib, pazopanib,regorafenib, brivanib, and vandetanib

Activation of intracellular signaling pathways is frequent in cancer,and agents targeting components of these pathways have been combinedwith receptor targeting agents to enhance efficacy and reduceresistance. Examples of agents that may be combined with compoundsdescribed herein include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway, andinhibitors of protein chaperones and cell cycle progression.

Agents against the PI3 kinase include but are not limited topilaralisib,idelalisib, buparlisib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus may be combined with KRAS inhibitors. Othersuitable examples include but are not limited to vemurafenib anddabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973(MEK inhibitors). Inhibitors of one or more JAKs (e.g., ruxolitinib,baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), HDACs (e.g., panobinostat), PARP (e.g.,olaparib), and proteasomes (e.g., bortezomib, carfilzomib) can also becombined with compounds described herein. In some embodiments, the JAKinhibitor is selective for JAK over JAK2 and JAK3.

Other suitable agents for use in combination with compounds describedherein include chemotherapy combinations such as platinum-based doubletsused in lung cancer and other solid tumors (cisplatin or carboplatinplus gemcitabine; cisplatin or carboplatin plus docetaxel; cisplatin orcarboplatin plus paclitaxel; cisplatin or carboplatin plus pemetrexed)or gemcitabine plus paclitaxel bound particles (Abraxane@).

Suitable chemotherapeutic or other anti-cancer agents include, forexample, alkylating agents (including, without limitation, nitrogenmustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas andtriazenes) such as uracil mustard, chlormethine, cyclophosphamide(Cytoxan™), ifosfamide, melphalan, chlorambucil, pipobroman,triethylene-melamine, triethylenethiophosphoramine, busulfan,carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

Other suitable agents for use in combination with compounds describedherein include steroids including 17 alpha-ethinylestradiol,diethylstilbestrol, testosterone, prednisone, fluoxymesterone,methylprednisolone, methyltestosterone, prednisolone, triamcinolone,chlorotrianisene, hydroxyprogesterone, aminoglutethimide, andmedroxyprogesteroneacetate.

Other suitable agents for use in combination with compounds describedherein include: dacarbazine (DTIC), optionally, along with otherchemotherapy drugs such as carmustine (BCNU) and cisplatin; the“Dartmouth regimen,” which consists of DTIC, BCNU, cisplatin andtamoxifen; a combination of cisplatin, vinblastine, and DTIC; ortemozolomide. Compounds described herein may also be combined withimmunotherapy drugs, including cytokines such as interferon alpha,interleukin 2, and tumor necrosis factor (TNF) in.

Suitable chemotherapeutic or other anti-cancer agents include, forexample, antimetabolites (including, without limitation, folic acidantagonists, pyrimidine analogs, purine analogs and adenosine deaminaseinhibitors) such as methotrexate, 5-fluorouracil, floxuridine,cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate,pentostatine, and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include,for example, certain natural products and their derivatives (forexample, vinca alkaloids, antitumor antibiotics, enzymes, lymphokinesand epipodophyllotoxins) such as vinblastine, vincristine, vindesine,bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin,idarubicin, ara-C, paclitaxel (TAXOL™), mithramycin, deoxycoformycin,mitomycin-C, L-asparaginase, interferons (especially IFN-α), etoposide,and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole,letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, anddroloxafine.

Also suitable are cytotoxic agents such as epidophyllotoxin; anantineoplastic enzyme; a topoisomerase inhibitor; procarbazine;mitoxantrone; platinum coordination complexes such as cis-platin andcarboplatin; biological response modifiers; growth inhibitors;antihormonal therapeutic agents; leucovorin; tegafur; and haematopoieticgrowth factors.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4, 4-1BB, PD-L1 and PD-1 antibodies, or antibodies to cytokines(IL-10, TGF-β, etc.).

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

Other anti-cancer agents also include those that augment the immunesystem such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNAvaccines and recombinant viruses. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). Non-limiting examples of tumorvaccines that can be used include peptides of melanoma antigens, such aspeptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, ortumor cells transfected to express the cytokine GM-CSF.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR, e.g., 1996edition, Medical Economics Company, Montvale, N.J.), the disclosure ofwhich is incorporated herein by reference as if set forth in itsentirety.

As provided throughout, the additional compounds, inhibitors, agents,etc. can be combined with the present compound in a single or continuousdosage form, or they can be administered simultaneously or sequentiallyas separate dosage forms.

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure can be administered in the form of pharmaceuticalcompositions. Thus, the present disclosure provides a compositioncomprising a compound of Formula I, II, or any of the formulas asdescribed herein, a compound as recited in any of the claims anddescribed herein, or a pharmaceutically acceptable salt thereof, or anyof the embodiments thereof, and at least one pharmaceutically acceptablecarrier or excipient. These compositions can be prepared in a mannerwell known in the pharmaceutical art, and can be administered by avariety of routes, depending upon whether local or systemic treatment isindicated and upon the area to be treated. Administration may be topical(including transdermal, epidermal, ophthalmic and to mucous membranesincluding intranasal, vaginal and rectal delivery), pulmonary (e.g., byinhalation or insufflation of powders or aerosols, including bynebulizer; intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the present disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers or excipients. In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208K100LV (e.g., Methocel K00LV™). Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 g/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

Labeled Compounds and Assay Methods Another aspect of the presentinvention relates to labeled compounds of the disclosure (radio-labeled,fluorescent-labeled, etc.) that would be useful not only in imagingtechniques but also in assays, both in vitro and in vivo, for localizingand quantitating KRAS protein in tissue samples, including human, andfor identifying KRAS ligands by inhibition binding of a labeledcompound. Substitution of one or more of the atoms of the compounds ofthe present disclosure can also be useful in generating differentiatedADME (Adsorption, Distribution, Metabolism and Excretion). Accordingly,the present invention includes KRAS binding assays that contain suchlabeled or substituted compounds.

The present disclosure further includes isotopically-labeled compoundsof the disclosure. An “isotopically” or “radio-labeled” compound is acompound of the disclosure where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present disclosure include but are not limited to ²H(also written as D for deuterium), ³H (also written as T for tritium),¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br,⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. For example, one or more hydrogenatoms in a compound of the present disclosure can be replaced bydeuterium atoms (e.g., one or more hydrogen atoms of a C₁₋₆ alkyl groupof Formula I or II can be optionally substituted with deuterium atoms,such as —CD₃ being substituted for —CH₃). In some embodiments, alkylgroups in Formula I or II can be perdeuterated.

One or more constituent atoms of the compounds presented herein can bereplaced or substituted with isotopes of the atoms in natural ornon-natural abundance. In some embodiments, the compound includes atleast one deuterium atom. In some embodiments, the compound includes twoor more deuterium atoms. In some embodiments, the compound includes 1-2,1-3, 1-4, 1-5, or 1-6 deuterium atoms. In some embodiments, all of thehydrogen atoms in a compound can be replaced or substituted by deuteriumatoms.

Synthetic methods for including isotopes into organic compounds areknown in the art (Deuterium Labeling in Organic Chemistry by Alan F.Thomas (New York, N.Y., Appleton-Century-Crofts, 1971; The Renaissanceof H/D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and JochenZimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistryof Isotopic Labelling by James R. Hanson, Royal Society of Chemistry,2011). Isotopically labeled compounds can be used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes, such as deuterium, may affordcertain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances. (seee.g., A. Kerekes et. al. J. Med. Chem. 2011, 54, 201-210; R. Xu et. al.J. Label Compd. Radiopharm. 2015, 58, 308-312). In particular,substitution at one or more metabolism sites may afford one or more ofthe therapeutic advantages.

The radionuclide that is incorporated in the instant radio-labeledcompounds will depend on the specific application of that radio-labeledcompound. For example, for in vitro adenosine receptor labeling andcompetition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹Ior ³⁵S can be useful. For radio-imaging applications ¹¹C ¹⁸F, ¹²⁵I,¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br can be useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments, the radionuclide is selected from ³H, ¹⁴C, ¹²⁵I, ³⁵S and⁸²Br.

The present disclosure can further include synthetic methods forincorporating radio-isotopes into compounds of the disclosure. Syntheticmethods for incorporating radio-isotopes into organic compounds are wellknown in the art, and an ordinary skill in the art will readilyrecognize the methods applicable for the compounds of disclosure.

A labeled compound of the invention can be used in a screening assay toidentify and/or evaluate compounds. For example, a newly synthesized oridentified compound (i.e., test compound) which is labeled can beevaluated for its ability to bind a KRAS protein by monitoring itsconcentration variation when contacting with the KRAS, through trackingof the labeling. For example, a test compound (labeled) can be evaluatedfor its ability to reduce binding of another compound which is known tobind to a KRAS protein (i.e., standard compound). Accordingly, theability of a test compound to compete with the standard compound forbinding to the KRAS protein directly correlates to its binding affinity.Conversely, in some other screening assays, the standard compound islabeled and test compounds are unlabeled. Accordingly, the concentrationof the labeled standard compound is monitored in order to evaluate thecompetition between the standard compound and the test compound, and therelative binding affinity of the test compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of diseases or disorders associated withthe activity of KRAS, such as cancer or infections, which include one ormore containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula I, II, or anyof the embodiments thereof. Such kits can further include one or more ofvarious conventional pharmaceutical kit components, such as, e.g.,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of KRAS according to at least one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check.

The compounds separated were typically subjected to analytical liquidchromatography mass spectrometry (LCMS) for purity check under thefollowing conditions: Instrument; Agilent 1100 series, LC/MSD, Column:Waters Sunfire™ C₁₈ 5 μm particle size, 2.1×5.0 mm, Buffers: mobilephase A: 0.025% TFA in water and mobile phase B: acetonitrile; gradient2% to 80% of B in 3 minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

-   -   pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size,        19×100 mm column, eluting with mobile phase A: 0.1% TFA        (trifluoroacetic acid) in water and mobile phase B:        acetonitrile; the flow rate was 30 mL/minute, the separating        gradient was optimized for each compound using the Compound        Specific Method Optimization protocol as described in the        literature [see “Preparative LCMS Purification: Improved        Compound Specific Method Optimization”, K. Blom, B. Glass, R.        Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically,        the flow rate used with the 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.”

The following abbreviations may be used herein: AcOH (acetic acid); Ac₂O(acetic anhydride); aq. (aqueous); atm. (atmosphere(s)); Boc(t-butoxycarbonyl); BOP((benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate); br (broad); Cbz (carboxybenzyl); calc.(calculated); d (doublet); dd (doublet of doublets); DBU(1,8-diazabicyclo[5.4.0]undec-7-ene); DCM (dichloromethane); DIAD(N,N′-diisopropyl azidodicarboxylate); DIEA (N,N-diisopropylethylamine);DIPEA or DIEA (N, N-diisopropylethylamine); DIBAL (diisobutylaluminiumhydride); DMF (N, N-dimethylformamide); Et (ethyl); EtOAc (ethylacetate); FCC (flash column chromatography); g (gram(s)); h (hour(s));HATU (N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate); HCl (hydrochloric acid); HPLC (high performanceliquid chromatography); Hz (hertz); IPA (isopropyl alcohol); J (couplingconstant); LCMS (liquid chromatography-mass spectrometry); LDA (lithiumdiisopropylamide); m (multiplet); M (molar); mCPBA(3-chloroperoxybenzoic acid); MS (Mass spectrometry); Me (methyl); MeCN(acetonitrile); MeOH (methanol); mg (milligram(s)); min. (minutes(s));mL (milliliter(s)); mmol (millimole(s)); N (normal); NCS(N-chlorosuccinimide); nM (nanomolar); NMP (N-methylpyrrolidinone); NMR(nuclear magnetic resonance spectroscopy); OTf(trifluoromethanesulfonate); Ph (phenyl); pM (picomolar); RP-HPLC(reverse phase high performance liquid chromatography); r.t. (roomtemperature), s (singlet); t (triplet or tertiary); TBS(tert-butyldimethylsilyl); tert (tertiary); tt (triplet of triplets);TFA (trifluoroacetic acid); THF (tetrahydrofuran); μg (microgram(s)); μL(microliter(s)); μM (micromolar); wt % (weight percent). Brine issaturated aqueous sodium chloride. In vacuo is under vacuum.

Example 1.1-Acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

Step 1. 3-Bromo-4-chloro-2-fluoroaniline

To a solution of 3-bromo-2-fluoroaniline (46.8 g, 246 mmol) in DMF (246ml) was added NCS (34.5 g, 259 mmol) portionwise, and the resultantmixture stirred at room temperature overnight. The mixture was pouredonto ice-water (400 mL) and extracted with ethyl acetate. The organiclayer was washed with water (2×), brine, dried over Na₂SO₄, filtered andconcentrated. The crude was purified with silica gel column (0-30% ethylacetate in hexanes) to give the desired product as brown oil whichsolidified on standing (38 g, 69%). LC-MS calculated for C₆H₅BrClFN(M+H)⁺: m/z=223.9, 225.9; found 223.9, 225.9.

Step 2. 7-Bromo-6-chloro-8-fluoroquinolin-4(IH)-one

The mixture of 3-bromo-4-chloro-2-fluoroaniline (1.3 g, 5.79 mmol),5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.186 g, 6.37mmol) and 2-propanol (12 ml) was heated at 90° C. for 2 h. The mixturewas cooled to room temperature, and the solid formed in the mixture wascollected by filtration, and washed with IPA (20 mL) and diethyl ether(20 mL) to give a colorless solid. The solid and DOWTHERM (25 mL) washeated at 220° C.-vigorous evolution of gas. The orange solution wasstirred at 220° C. for 40 min then cooled to room temperature. To themixture was added heptane (25 mL), and the mixture was filtered, withthe solid collected, washed with heptane and ethyl ether and dried undervacuum to give the desired product as a tan solid (2.1 g, 96%). LC-MScalculated for C₉H₅BrClFNO (M+H)⁺: m/z=275.9, 277.9; found 275.9, 277.9.

Step 3. 7-Bromo-6-chloro-8-fluoro-3-nitroquinolin-4(1H)-one

7-Bromo-6-chloro-8-fluoroquinolin-4(1H)-one (804 mg, 2.91 mmol) wasadded to stirred propionic acid (7.86 ml) and the mixture was heated at125° C. with stirring. Nitric acid (260 μl, 5.82 mmol) was addeddropwise, and the solution was stirred for 2 hours at 125° C. beforebeing allowed to cool to room temperature. Water was added, and themixture was filtered. The solid collected was washed with water anddiethyl ether then dried to give the desired product as a pale solid(0.57 g, 61%). LC-MS calculated for CH₄BrClFN₂O₃ (M+H)⁺: m/z=320.9,322.9; found 320.9, 322.8.

Step 4. 7-Bromo-4,6-dichloro-8-fluoro-3-nitroquinoline

POCl₃ (0.893 ml, 9.58 mmol) was added to7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-ol (0.77 g, 2.395 mmol) intoluene (14 ml) at room temperature. The mixture was heated at 110° C.with stirring, at which point DMF (0.1 mL) was added and the mixture wasstirred at 110° C. overnight. The solvents were removed by evaporation.Toluene (15 mL) was added and the solvents evaporated. The residue wastaken up in DCM (100 mL) and poured into ice-cold sat NaHCO₃ (150 mL).The mixture was extracted with DCM (3×). The combined organic layerswere washed with brine, dried and evaporated to give the desired productas light brown solid (0.80 g, 98%). LC-MS calculated for C₉H₃BrCl₂FN₂O₂(M+H)⁺: m/z=338.9, 340.9; found 338.9, 340.9.

Step 5. 1-(tert-Butyl)-4-methyl4-((7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-yl)amino)-piperidine-1,4-dicarboxylate

To a solution of 7-bromo-4,6-dichloro-8-fluoro-3-nitroquinoline (330 mg,0.971 mmol), 1-(tert-butyl) 4-methyl 4-aminopiperidine-1,4-dicarboxylate(301 mg, 1.165 mmol) in DMF (3.24 ml) was added DIEA (424 μl, 2.427mmol). The mixture was stirred at 40° C. for 2 hours. The reactionmixture was diluted with ethyl acetate and water. The organic layer wasseparated and concentrated. The residue was purified with silica gelcolumn to give the desired product (0.32 g, 59%). LC-MS calculated forC₂₁H₂₄BrClFN₄O₆ (M+H)⁺: m/z=561.1, 563.1; found 561.1, 563.1.

Step 6. tert-Butyl8′-bromo-9′-chloro-7′-fluoro-3′-oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinoline]-1-carboxylate

To a solution of 1-(tert-butyl) 4-methyl4-((7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-yl)amino)piperidine-1,4-dicarboxylate(320 mg, 0.570 mmol) in acetic acid (2.0 ml) was added iron (159 mg,2.85 mmol). The resulting mixture was stirred at 80° C. for 1 h. Themixture was filtered through a pad of Celite and washed with methanol.The filtrate was concentrated and purified with silica gel column (0.19g, 68%). LC-MS calculated for C₂₀H₂₂BrClFN₄O₃ (M+H)⁺: m/z=499.1, 501.1;found 499.1, 501.1.

Step 7.1-Acryloyl-8′-bromo-9′-chloro-7′-fluoro-1′4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

To a reaction mixture of tert-butyl8′-bromo-9′-chloro-7′-fluoro-3′-oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinoline]-1-carboxylate(194 mg, 0.388 mmol) and DCM (1.0 mL) was added TFA (1.2 mL, 15.53mmol). After stirring for 1 hour at room temperature, the volatiles wereremoved under reduced pressure. The residue was dissolved in DCM (1.0mL) and 1.0 M acryloyl chloride in DCM (466 μl, 0.466 mmol) was added,followed by DIEA (339 μl, 1.941 mmol) at 0° C. After stirring at sametemperature for 0.5 h, the reaction mixture was diluted with ethylacetate and water. The aqueous layer was extracted with ethyl acetateonce. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude was purified with flashchromatography to yield the desired product (125 mg, 71%). LC-MScalculated for C₁₈H₁₆BrClFN₄O₂ (M+H)⁺: m/z=453.0, 455.0; found 453.0,455.0.

Step 8.1-Acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

A mixture of1-acryloyl-8′-bromo-9′-chloro-7′-fluoro-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one(12 mg, 0.026 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (9.07 mg,0.058 mmol), tetrakis (3.06 mg, 2.64 μmol) and tripotassium phosphatehydrate (13.40 mg, 0.058 mmol) in 1,4-Dioxane (1.0 mL)/Water (0.200 mL)was stirred at 80° C. for 2 h. The residue was dissolved in methanol and1 N HCl and purified with prep-LCMS (pH 2, acetonitrile/water+TFA) togive the product as a pair of atropisomers as TFA salt. LC-MS calculatedfor C₂₄H₂₀ClF₂N₄O₃ (M+H)⁺: m/z=485.2; found 485.2.

Example 2.1-Acryloyl-9′-chloro-8′-(2-chloro-5-hydroxyphenyl)-7′-fluoro-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

This compound was prepared using similar procedures as described forExample 1, with (2-chloro-5-hydroxyphenyl)boronic acid replacing(2-fluoro-6-hydroxyphenyl)boronic acid in Step 8. The reaction mixturewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as TFA salt. LC-MS calculated for C₂₄H₂₀Cl₂FN₄O₃ (M+H)⁺:m/z=501.1; found 501.1.

Example 3.1-Acryloyl-9′-chloro-7′-fluoro-8′-(3-methyl-1H-indazol-4-yl)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

This compound was prepared using similar procedures as described forExample 1, with (3-methyl-1H-indazol-4-yl)boronic acid replacing(2-fluoro-6-hydroxyphenyl)boronic acid in Step 8. The reaction mixturewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as a pair of atropisomers as TFA salt. LC-MS calculatedfor C₂₆H₂₃ClFN₆O₂ (M+H)⁺: m/z=505.2; found 505.2.

Example 4.1-Acryloyl-9′-chloro-7′-fluoro-8′-(5-methyl-1H-indazol-4-yl)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

This compound was prepared using similar procedures as described forExample 1, with5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazolereplacing (2-fluoro-6-hydroxyphenyl)boronic acid in Step 8. The reactionmixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as a pair of atropisomers as TFA salt. LC-MScalculated for C₂₆H₂₃ClFN₆O₂ (M+H)⁺: m/z=505.2; found 505.2.

Example 5.1-Acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-methoxyphenyl)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

This compound was prepared using similar procedures as described forExample 1, with (2-fluoro-6-methoxyphenyl)boronic acid replacing(2-fluoro-6-hydroxyphenyl)boronic acid in Step 8. The reaction mixturewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as a pair of atropisomers as TFA salt. LC-MS calculatedfor C₂₅H₂₂ClF₂N₄O₃ (M+H)⁺: m/z=499.1; found 499.1.

Example 6.1-Acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-1′,4′-dihydro-3′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one

Step 1. 1-(tert-Butyl) 3-ethyl3-((7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-yl)amino)azetidine-1,3-dicarboxylate

This compound was prepared using similar procedures as described forExample 1, with 1-(tert-butyl) 3-ethyl3-aminoazetidine-1,3-dicarboxylate replacing 1-(tert-butyl) 4-methyl4-aminopiperidine-1,4-dicarboxylate in Step 5. LC-MS calculated forC₂H₂₂BrClFN₄O₆ (M+H)⁺: m/z=547.0, 549.0; found 547.0, 549.0.

Step 2. tert-Butyl8′-bromo-9′-chloro-7′-fluoro-3′-oxo-3′,4′-dihydro-1′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 1, with tert-butyl8′-bromo-9′-chloro-7′-fluoro-3′-oxo-3′,4′-dihydro-1′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl8′-bromo-9′-chloro-7′-fluoro-3′-oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinoline]-1-carboxylatein Step 6. LC-MS calculated for C₁₈H₁₈BrClFN₄O₃ (M+H)⁺: m/z=471.0,473.0; found 471.0, 473.0.

Step 3.1-Acryloyl-8′-bromo-9′-chloro-7′-fluoro-1′4′-dihydro-3′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one

This compound was prepared using similar procedures as described forExample 1, with tert-butyl8′-bromo-9′-chloro-7′-fluoro-3′-oxo-3′,4′-dihydro-1′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl8′-bromo-9′-chloro-7′-fluoro-3′-oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinoline]-1-carboxylatein Step 6. LC-MS calculated for C₁₆H₁₂BrClFN₄O₂ (M+H)⁺: m/z=425.0,427.0; found 425.0, 427.0.

Step 4.1-Acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-1′,4′-dihydro-3′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one

A microwave vial charged with1-acryloyl-8′-bromo-9′-chloro-7′-fluoro-1′,4′-dihydro-3′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one(20 mg, 0.047 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (16.12 mg,0.103 mmol), tetrakis (5.43 mg, 4.70 μmol) and potassium carbonate(19.48 mg, 0.141 mmol) in 1,4-dioxane (1.0 mL) and water (0.200 mL) wassealed with Teflon cap. The vial was evacuated under high vacuum andrefilled with nitrogen (repeated three times). The reaction mixture wasstirred at 80° C. for 2 h. The reaction solution was diluted withmethanol and 1 N HCl and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the product as a pair of atropisomers asTFA salt. LC-MS calculated for C₂₂H₁₆ClF₂N₄O₃ (M+H)⁺: m/z=457.1; found457.2.

Example 7.1-Acryloyl-9′-chloro-7′-fluoro-8′-(5-methyl-1H-indazol-4-yl)-1′,4′-dihydro-3′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one

This compound was prepared using similar procedures as described forExample 6, with5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazolereplacing (2-fluoro-6-hydroxyphenyl)boronic acid in Step 4. The reactionmixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as a pair of atropisomers as TFA salt. LC-MScalculated for C₂₄H₁₉ClFN₆O₂ (M+H)⁺: m/z=477.1; found 477.1.

Example 8.1′-Acryloyl-9-chloro-7-fluoro-8-(2-fluoro-6-hydroxyphenyl)-1,4-dihydro-3H-spiro[pyrazino[2,3-c]quinoline-2,3′-pyrrolidin]-3-one

Step 1. 1-(tert-Butyl) 3-methyl3-((7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-yl)amino)-pyrrolidine-1,3-dicarboxylate

This compound was prepared using similar procedures as described forExample 1, with 1-(tert-butyl) 3-methyl3-aminopyrrolidine-1,3-dicarboxylate replacing 1-(tert-butyl) 4-methyl4-aminopiperidine-1,4-dicarboxylate in Step 5. LC-MS calculated forC₂₀H₂₂BrClFN₄O₆ (M+H)⁺: m/z=547.0, 549.0; found 547.0, 549.0.

Step 2. tert-Butyl8-bromo-9-chloro-7-fluoro-3-oxo-3,4-dihydro-1H-spiro[pyrazino[2,3-c]quinoline-2,3′-pyrrolidine]-1′-carboxylate

This compound was prepared using similar procedures as described forExample 1, with 1-(tert-butyl) 3-methyl3-((7-bromo-6-chloro-8-fluoro-3-nitroquinolin-4-yl)amino)pyrrolidine-1,3-dicarboxylatereplacing tert-butyl8′-bromo-9′-chloro-7′-fluoro-3′-oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinoline]-1-carboxylatein Step 6. LC-MS calculated for C₁₉H₂₀BrClFN₄O₃ (M+H)⁺: m/z=485.0,487.0; found 485.0, 487.0.

Step 3.1′-Acryloyl-8-bromo-9-chloro-7-fluoro-1,4-dihydro-3H-spiro[pyrazino[2,3-c]quinoline-2,3′-pyrrolidin]-3-one

This compound was prepared using similar procedures as described forExample 1, with tert-butyl8-bromo-9-chloro-7-fluoro-3-oxo-3,4-dihydro-1H-spiro[pyrazino[2,3-c]quinoline-2,3′-pyrrolidine]-1′-carboxylatereplacing tert-butyl8′-bromo-9′-chloro-7′-fluoro-3′-oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinoline]-1-carboxylatein Step 7. LC-MS calculated for C₁₇H₁₄BrClFN₄O₂ (M+H)⁺: m/z=439.0,441.0; found 439.0, 441.0.

Step 4.1′-Acryloyl-9-chloro-7-fluoro-8-(2-fluoro-6-hydroxyphenyl)-1,4-dihydro-3H-spiro[pyrazino[2,3-c]quinoline-2,3′-pyrrolidin]-3-one

A microwave vial charged with1′-acryloyl-8-bromo-9-chloro-7-fluoro-1,4-dihydro-3H-spiro[pyrazino[2,3-c]quinoline-2,3′-pyrrolidin]-3-one(24 mg, 0.055 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (18.72 mg,0.120 mmol), tetrakis (6.31 mg, 5.46 μmol) and potassium carbonate(22.63 mg, 0.164 mmol) in 1,4-dioxane (1.0 mL) and water (0.200 mL) wassealed with Teflon cap. The vial was evacuated under high vacuum andrefilled with nitrogen (repeated three times). The reaction mixture wasstirred at 80° C. for 2 h. The reaction solution was diluted withmethanol and 1 N HCl and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the product as a mixture ofdiastereomers as TFA salt. LC-MS calculated for C₂₃H₁₈ClF₂N₄O₃ (M+H)⁺:m/z=471.1; found 471.2.

Example 9.1′-Acryloyl-9-chloro-7-fluoro-8-(5-methyl-1H-indazol-4-yl)-1,4-dihydro-3H-spiro[pyrazino[2,3-c]quinoline-2,3′-pyrrolidin]-3-one

This compound was prepared using similar procedures as described forExample 8, with5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazolereplacing (2-fluoro-6-hydroxyphenyl)boronic acid in Step 4. The reactionmixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as a mixture of diastereomers as TFA salt. LC-MScalculated for C₂₅H₂₁ClFN₆O₂ (M+H)⁺: m/z=491.1; found 491.1.

Example 10.1-Acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-5′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

Step 1. 2-Amino-4-bromo-5-chloro-3-fluorobenzoic acid

To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (10.02 g, 42.8mmol) in DMF (143 ml) was added NCS (6.29 g, 47.1 mmol) at roomtemperature. The mixture was heated at 70° C. for 2 h. The reactionmixture was cooled to room temperature, and diluted with water. Theprecipitate was collected with filtration and washed with water andethyl acetate/hexane (1:2). The filtrate was acidified with 1 N HCl andextracted with ethyl acetate. The organic layer was concentrated. Thesolid was collected with filtration and washed ethyl acetate/hexane(1:2) (10.6 g, 92%). LC-MS calculated for C₇HBrClFNO₂ (M+H)⁺: m/z=267.9,269.9; found 267.9, 269.9.

Step 2. 7-Bromo-6-chloro-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione

To a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (9.10 g,33.9 mmol) in THF (113 ml) was added triphosgene (3.42 g, 11.52 mmol).The resulting solution was stirred at room temperature overnight. LCMSshowed completion of reaction. The most solvent was removed underreduced pressure. The reaction solution was diluted with hexanes. Theresulting precipitate was collected via filtration and dried undervacuum (9.1 g, 91%). LC-MS calculated for C₈H₃BrClFNO₃ (M+H)⁺:m/z=293.9, 295.9; found 294.0, 296.0.

Step 3. 7-Bromo-6-chloro-8-fluoro-4-hydroxy-3-nitroquinolin-2(1H)-one

To a solution of7-bromo-6-chloro-8-fluoro-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (9.0 g,30.6 mmol) in DMF (153 ml) was added ethyl 2-nitroacetate (6.79 ml, 61.1mmol) and DIEA (10.68 ml, 61.1 mmol). The resulting mixture was stirredat 95° C. for 4 h. LCMS showed the desired product and compound A washydrolyzed back to acid. The reaction mixture was cooled to rt anddiluted with ethyl acetate and water. The compound C was in aqueouslayer. The aqueous layer was concentrated and resulting precipitate wascollected via filtration and washed with ethyl acetate/hexanes (1:1)(4.6 g, 45%). LC-MS calculated for C₉H₄BrClFN₂O₄ (M+H)⁺: m/z=336.9,338.9; found 336.9, 338.9.

Step 4. 7-Bromo-2,4,6-trichloro-8-fluoro-3-nitroquinoline

DIEA (0.558 ml, 3.19 mmol) was added to7-bromo-6-chloro-8-fluoro-3-nitroquinoline-2,4-diol (0.539 g, 1.597mmol) in toluene (9.2 ml) at room temperature. The mixture was cooled to0° C., and POCl₃ (0.744 ml, 7.99 mmol) was added. The mixture was heatedat 110° C. with stirring for 1 h. The solvents were removed byevaporation. Toluene (15 mL) was added and the solvents evaporated. Theresidue was taken up in DCM (100 mL) and poured into ice-cold satNaHCO₃(150 mL). The mixture was extracted with DCM once. The combinedorganic layers were washed with brine, dried and evaporated. The crudepurified with silica gel column to give the title compound.

Step 5. 1-(tert-Butyl) 4-methyl4-((7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)amino)piperidine-1,4-dicarboxylate

To a solution of 7-bromo-2,4,6-trichloro-8-fluoro-3-nitroquinoline (1.74g, 4.65 mmol), 1-(tert-butyl) 4-methyl4-aminopiperidine-1,4-dicarboxylate (1.801 g, 6.97 mmol) in DMF (15 ml)was added DIEA (2.03 ml, 11.62 mmol). The mixture was stirred at 50° C.overnight. The reaction mixture was diluted with ethyl acetate andwater. The organic layer was separated and concentrated. The residue waspurified with silica gel column to give the desired product (1.2 g,43%). LC-MS calculated for C₂₁H₂₃BrCl₂FN₄O₆ (M+H)⁺: m/z=595.1, 597.1;found 595.1, 597.1.

Step 6. 1-(tert-Butyl) 4-methyl(S)-4-((7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-3-nitroquinolin-4-yl)amino)piperidine-1,4-dicarboxylate

To a solution of (S)-(1-methylpyrrolidin-2-yl)methanol (46.4 mg, 0.403mmol) in THF (2 ml) was added 60% sodium hydride (20.1 mg, 0.503 mmol).The mixture was stirred at 0° C. for 0.5 h, 1-(tert-butyl) 4-methyl4-((7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)amino)piperidine-1,4-dicarboxylate(120 mg, 0.201 mmol) was added to reaction vial and mixture was stirredfor 1 h at rt. The reaction mixture was diluted with ethyl acetate andwater. The organic layer was separated and concentrated. The crude wasused in the next step without further purification. LC-MS calculated forC₂₇H₃₅BrClFN₅O₇ (M+H)⁺: m/z=674.1, 676.1; found 674.1, 676.1.

Step 7. tert-Butyl(S)-8′-bromo-9′-chloro-7′-fluoro-5′-((1-methylpyrrolidin-2-yl)methoxy)-3′-oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinoline]-1-carboxylate

To a solution of 1-(tert-butyl) 4-methyl(S)-4-((7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-3-nitroquinolin-4-yl)amino)piperidine-1,4-dicarboxylate(136 mg, 0.201 mmol) in acetic acid (2.0 ml) was added iron (56.3 mg,1.007 mmol). The resulting mixture was stirred at 80° C. for 1 h, themixture was filtered through a pad of Celite and washed with methanol.The filtrate was concentrated and purified with silica gel column toyield the desired product (124 mg, 100%). LC-MS calculated forC₂₆H₃₃BrClFNO₄ (M+H)⁺: m/z=612.1, 614.1; found 612.1, 614.1.

Step 8.(S)-1-Acryloyl-8′-bromo-9′-chloro-7′-fluoro-5′-((1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

To a reaction mixture of tert-butyl(S)-8′-bromo-9′-chloro-7′-fluoro-5′-((1-methylpyrrolidin-2-yl)methoxy)-3′-oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinoline]-1-carboxylate(124 mg, 0.202 mmol) and DCM (1.0 ml) was added TFA (623 μl, 8.09 mmol).After stirring for 1 hour at room temperature, the volatiles wereremoved under reduced pressure. The residue was dissolved in DCM (1.0ml) and 1.0 M acryloyl chloride in DCM (243 μl, 0.243 mmol) was added,followed by DIEA (70.7 μl, 0.405 mmol) at 0° C. After stirring at sametemperature for 0.5 h, the reaction mixture was diluted with ethylacetate and water. The aqueous layer was extracted with ethyl acetateonce. The combined organic layers were washed with brine, dried overNa₂SO₄, filtered and concentrated. The crude was purified with prep-LCMS(pH 2, acetonitrile/water+TFA) to yield the desired product (45 mg,43%). LC-MS calculated for C₂₄H₂₇BrClFN₅O₃ (M+H)⁺: m/z=566.1, 568.1;found 566.1, 568.1.

Step 9.1-Acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-5′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

A mixtureof(S)-1-acryloyl-8′-bromo-9′-chloro-7′-fluoro-5′-((1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one(28mg, 0.049 mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (16.94 mg, 0.109mmol), tetrakis (5.71 mg, 4.94 μmol) and sodium carbonate (5.24 mg,0.049 mmol) in 1,4-dioxane (1.0 mL)/water (0.20 mL) was stirred at 80°C. for 2 h. The reaction solution was dissolved in methanol and 1 N HCland purified with prep-LCMS (pH 2, acetonitrile/water+TFA) to give theproduct as a mixture of diastereomers as TFA salt. LC-MS calculated forC₃₀H₃₁ClF₂N₅O₄ (M+H)⁺: m/z=598.2; found 598.2.

Example 11.1-Acryloyl-9′-chloro-7′-fluoro-8′-(3-hydroxynaphthalen-1-yl)-5′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

This compound was prepared using similar procedures as described forExample 10, with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol replacing(2-fluoro-6-hydroxyphenyl)boronic acid in Step 9. The reaction mixturewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as a mixture of diastereomers as TFA salt. LC-MScalculated for C₃₄H₃₄ClFN₅O₄ (M+H)⁺: m/z=630.2; found 630.2. ¹H NMR (500MHz, DMSO) δ 10.30 (s, 1H), 9.99 (s, 1H), 8.52 (s, 1H), 7.81 (d, J=8.3Hz, 1H), 7.44 (t, J=7.4 Hz, 1H), 7.29 (s, 2H), 7.25-7.15 (m, 2H), 7.07(s, 1H), 6.87 (m, 1H), 6.16 (d, J=16.7 Hz, 1H), 5.73 (d, J=10.6 Hz, 1H),4.90-4.82 (m, 1H), 4.70 (bs, 1H), 4.05-3.75 (m, 5H), 3.71 (m, 2H),3.62-3.12 (m, 2H), 2.99 (d, J=4.6 Hz, 3H), 2.25-1.67 (m, 8H).

Example 12.1-Acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-5′-(2-(piperidin-1-yl)ethoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

Step 1. 1-(tert-Butyl) 4-methyl4-((7-bromo-6-chloro-8-fluoro-3-nitro-2-(2-(piperidin-1-yl)ethoxy)quinolin-4-yl)amino)piperidine-1,4-dicarboxylate

This compound was prepared using similar procedures as described forExample 10, with 2-(piperidin-1-yl)ethan-1-ol replacing(S)-(1-methylpyrrolidin-2-yl)methanol in Step 6. LC-MS calculated forC₂₈H₃₇BrClFN₅O₇ (M+H)⁺: m/z=688.2, 690.2; found 688.2, 690.2.

Step 2. tert-Butyl8′-bromo-9′-chloro-7′-fluoro-3′-oxo-5′-(2-(piperidin-1-yl)ethoxy)-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 10, with 1-(tert-butyl) 4-methyl4-((7-bromo-6-chloro-8-fluoro-3-nitro-2-(2-(piperidin-1-yl)ethoxy)quinolin-4-yl)amino)piperidine-1,4-dicarboxylatereplacing 1-(tert-butyl) 4-methyl(S)-4-((7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-3-nitroquinolin-4-yl)amino)piperidine-1,4-dicarboxylatein Step 7. LC-MS calculated for C₂₇H₃₅BrClFN₅O₄ (M+H)⁺: m/z=626.2,628.1; found 626.2, 628.2.

Step 3.1-Acryloyl-8′-bromo-9′-chloro-7′-fluoro-5′-(2-(piperidin-1-yl)ethoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

This compound was prepared using similar procedures as described forExample 10, with tert-butyl8′-bromo-9′-chloro-7′-fluoro-3′-oxo-5′-(2-(piperidin-1-yl)ethoxy)-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl(S)-8′-bromo-9′-chloro-7′-fluoro-5′-((1-methylpyrrolidin-2-yl)methoxy)-3′-oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinoline]-1-carboxylatein Step 8. LC-MS calculated for C₂₅H₂₉BrClFN₅O₃ (M+H)⁺: m/z=580.1,582.1; found 580.1, 582.1.

Step 4.1-Acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-5′-(2-(piperidin-1-yl)ethoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one

This compound was prepared using similar procedures as described forExample 10, with1-acryloyl-8′-bromo-9′-chloro-7′-fluoro-5′-(2-(piperidin-1-yl)ethoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-onereplacing(S)-1-acryloyl-8′-bromo-9′-chloro-7′-fluoro-5′-((1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-onein Step 9. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as a mixture ofdiastereomers as TFA salt. LC-MS calculated for C₃₁H₃₃ClF₂N₅O₄ (M+H)⁺:m/z=612.2; found 612.2.

Example 13.1-Acryloyl-8′-chloro-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)spiro[piperidine-4,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

Step 1. 1-(tert-Butyl) 4-methyl4-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)piperidine-1,4-dicarboxylate

7-Bromo-2,4,6-trichloro-8-fluoro-3-nitroquinoline (Example 10, Step 4,100 mg, 0.267 mmol) and 1-(tert-butyl) 4-methylpiperidine-1,4-dicarboxylate (130 mg, 0.534 mmol) were combined and THF(2 ml) was added. The solution was cooled to −78° C. then KHMDS (0.5 M,in toluene, 1068 μl, 0.534 mmol) was added. The mixture was stirred at−78° C. for 10 min, then quenched with saturated aqueous NH₄Cl, dilutedwith EtOAc, separated. The aqueous layer was extracted with EtOAc andthe combined organic layer was washed with brine, dried over Na₂SO₄,filtered and evaporated. The residue was purified with columnchromatography (0-50% ethyl acetate in hexanes) to give the desiredproduct as a brown solid. LC-MS calculated for C₁₆H₁₄BrCl₂FN₃O₄(M-Boc+H)⁺: m/z=480.0; found 480.0.

Step 2. 1-(tert-Butyl) 4-methyl(S)-4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-3-nitroquinolin-4-yl)piperidine-1,4-dicarboxylate

(S)-(1-Methylpyrrolidin-2-yl)methanol (49.0 μl, 0.413 mmol) in THF (2ml) was added NaH (16.52 mg, 0.413 mmol) at 0° C. After stirring at 0°C. for 30 min, 1-(tert-butyl) 4-methyl4-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)piperidine-1,4-dicarboxylate(120 mg, 0.206 mmol) was added. The mixture was stirred at roomtemperature for 1 h, then quenched with saturated aqueous NH₄Cl, dilutedwith EtOAc, separated. The aqueous layer was extracted with EtOAc andthe combined organic layer was washed with brine, dried over Na₂SO₄,filtered and evaporated to give the desired product as a brown solid.The residue was used without further purification. LC-MS calculated forC₂₇H₃₄BrClFN₄O₇ (M+H)⁺: m/z=659.2; found 659.2.

Step 3.tert-Butyl(S)-7′-bromo-8′-chloro-6′-fluoro-4′-((1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-4,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

To a solution of 1-(tert-butyl) 4-methyl(S)-4-(7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-3-nitroquinolin-4-yl)piperidine-1,4-dicarboxylate(100 mg, 0.152 mmol) in acetic acid (2.0 ml) was added Fe (42.3 mg,0.758 mmol). The resulting mixture was stirred at 80° C. for 1 h. Themixture was filtered through a pad of Celite and washed with methanol.The filtrate was concentrated and purified with silica gel columnchromatography (0-10% MeOH in DCM) to give the desired product as awhite solid. LC-MS calculated for C₂₆H₃₂BrClFN₄O₄ (M+H)⁺: m/z=597.1;found 597.1.

Step 4.(S)-1-Acryloyl-7′-bromo-8′-chloro-6′-fluoro-4′-((1-methylpyrrolidin-2-yl)methoxy)-spiro[piperidine-4,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

4N HCl (1.0 mL) was added to a solution of tert-butyl(S)-7′-bromo-8′-chloro-6′-fluoro-4′-((1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-4,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(50 mg, 0.084 mmol) in DCM/MeOH (0.5/0.5 mL) and stirred at roomtemperature for 30 min. The solvent was removed under vacuum. Theresidue was dissolved in DCM (2.0 ml) and cooled to 0° C., to this wasadded triethylamine (69.9 μl, 0.502 mmol) followed by acryloyl chloride(6.76 μl, 0.084 mmol) and the reaction was stirred at 0° C. for 20 min.The reaction was diluted with DCM and washed with saturated NaHCO₃,separated; the organic layer was dried over Na₂SO₄ and concentrated. Theproduct was purified by silica gel column chromatography (0-10% MeOH inDCM) to give the desired product as a white solid. LC-MS calculated forC₂₄H₂₆BrClFN₄O₃ (M+H)⁺: m/z=551.1; found 551.1.

Step 5.1-Acryloyl-8′-chloro-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)spiro[piperidine-4,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

A mixture of(S)-1-acryloyl-7′-bromo-8′-chloro-6′-fluoro-4′-((1-methylpyrrolidin-2-yl)methoxy)spiro[piperidine-4,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one(20 mg, 0.036 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (29.4 mg,0.109 mmol), sodium carbonate (19.21 mg, 0.181 mmol) and Pd(PPh₃)₄(12.56 mg, 10.87 μmol) in Dioxane (0.8 ml)/Water (0.200 ml) was vacuumedand refilled with N₂ twice and then the reaction was stirred at 95° C.for 2 h. The reaction mixture was cooled to room temperature, quenchedand acidified with TFA, filtered and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as a mixture ofdiastereomers as TFA salt. LC-MS calculated for C₃₄H₃₃ClFN₄O₄ (M+H)⁺:m/z=615.2; found 615.2.

Example 14.1-Acryloyl-8′-chloro-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)spiro[pyrrolidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

This compound was prepared using similar procedures as described forExample 13, with 1-(tert-butyl) 3-ethyl pyrrolidine-1,3-dicarboxylatereplacing 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate inStep 1. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the product as a mixture ofdiastereomers as TFA salt. LC-MS calculated for C₃₃H₃₁ClFN₄O₄ (M+H)⁺:m/z=601.2; found 601.2.

Example 15.1-Acryloyl-8′-chloro-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)spiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

This compound was prepared using similar procedures as described forExample 13, with 1-(tert-butyl) 3-methyl piperidine-1,3-dicarboxylatereplacing 1-(tert-butyl) 4-methyl piperidine-1,4-dicarboxylate inStep 1. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the product as a mixture ofdiastereomers as TFA salt. LC-MS calculated for C₃₄H₃₃ClFN₄O₄ (M+H)⁺:m/z=615.2; found 615.2.

Example 16a and Example 16b.1-Acryloyl-8′-chloro-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-3′-methyl-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)spiro[piperidine-4,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

Step 1.tert-Butyl(S)-7′-bromo-8′-chloro-6′-fluoro-3′-methyl-4′-((1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-4,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

To a solution of tert-butyl(S)-7′-bromo-8′-chloro-6′-fluoro-4′-((1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-4,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(Example 13, Step 3) (30 mg, 0.050 mmol) in DMF (1 ml) was added NaH(60% in mineral oil, 4.01 mg, 0.100 mmol) at 0° C. After stirring at 0°C. for 30 min, Mel (15.69 μl, 0.251 mmol) was added. The mixture wasstirred room temperature for 1 h then quenched with water, extractedwith EtOAc, separated; the organic layer was dried over Na₂SO₄ andconcentrated. The product was purified by silica gel columnchromatography (0-10% MeOH in DCM) to give the desired product as awhite solid. LC-MS calculated for C₂₇H₃₄BrClFN₄O₄ (M+H)⁺: m/z=611.1;found 611.1.

Step 2.1-Acryloyl-8′-chloro-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-3′-methyl-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)spiro[piperidine-4,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

This compound was prepared using similar procedures as described forExample 13, with tert-butyl(S)-7′-bromo-8′-chloro-6′-fluoro-3′-methyl-4′-((1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-4,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl(S)-7′-bromo-8′-chloro-6′-fluoro-4′-((1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-4,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatein Step 4. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired products as TFA salt.

Example 16a. Diastereomer 1. Peak 1. LC-MS calculated for C₃₅H₃₅ClFN₄O₄(M+H)⁺: m/z=629.2; found 629.2.

Example 16b. Diastereomer 2. Peak 2. LC-MS calculated for C₃₅H₃₅ClFN₄O₄(M+H)⁺: m/z=629.2; found 629.2.

Example 17.1-Acryloyl-9′-chloro-7′-fluoro-8′-(3-hydroxynaphthalen-1-yl)spiro[piperidine-4,2′-pyrano[3,2-c]quinolin]-4′(3′H)-one

Step 1. Ethyl(Z)-2-(((3-bromo-4-chloro-2-fluorophenyl)amino)methylene)-3-oxobutanoate

A stirred mixture of ethyl 3-oxobutanoate (3.16 ml, 24.95 mmol),triethyl orthoformate (4.99 ml, 29.9 mmol), and3-bromo-4-chloro-2-fluoroaniline (Example 1, Step 1) (5.60 g, 24.95mmol) were heated at 150° C. for 16 h with a Dean Stark trap. After thistime the reaction was cooled to room temperature and the resultingprecipitate was suspended in 1:1 ether/hexanes, and filtered to affordthe desired product (5.3 g, 58%). LC-MS calculated for C₁₃H₁₃BrClFNO₃(M+H)⁺: m/z=364.0, 366.0; found=364.0, 366.0.

Step 2. 1-(7-Bromo-6-chloro-8-fluoro-4-hydroxyquinolin-3-yl)ethan-1-one

A microwave vial charged with ethyl(Z)-2-(((3-bromo-4-chloro-2-fluorophenyl)-amino)methylene)-3-oxobutanoate(1.00 g, 2.74 mmol) and diphenyl ether (10 ml) was heated at 260° C. for1 h. After cooling to room temperature, mixture was added heptane (25mL), and the mixture was filtered, with the solid collected, washed withheptane and ethyl ether and dried under vacuum to give the desiredproduct as a tan solid (0.7 g, 80%). LC-MS calculated for CH₇BrClFNO₂(M+H)⁺: m/z=318.0, 320.0; found==318.0, 320.0.

Step 3. tert-Butyl8′-bromo-9′-chloro-7′-fluoro-4′-oxo-3′,4′-dihydrospiro[piperidine-4,2′-pyrano[3,2-c]quinoline]-1-carboxylate

To a solution of1-(7-bromo-6-chloro-8-fluoro-4-hydroxyquinolin-3-yl)ethan-1-one (645 mg,2.025 mmol) in MeOH (6.14 ml) was added tert-butyl4-oxopiperidine-1-carboxylate (403 mg, 2.025 mmol) and pyrrolidine (335μl, 4.05 mmol). The resulting mixture was heated at 80° C. overnight.The solvent was removed and the crude was purified with flashchromatography (eluting with 0-60% ethyl acetate in hexanes) to give thedesired product (0.2 g, 20%). LC-MS calculated for C₂₁H₂₂BrClFN₂O₄(M+H)⁺: m/z=499.0, 501.0; found 499.1, 501.1.

Step 4.1-Acryloyl-8′-bromo-9′-chloro-7′-fluorospiro[piperidine-4,2′-pyrano[3,2-c]quinolin]-4′(3′H)-one

To a solution of tert-butyl8′-bromo-9′-chloro-7′-fluoro-4′-oxo-3′,4′-dihydrospiro[piperidine-4,2′-pyrano[3,2-c]quinoline]-1-carboxylate(34 mg, 0.068 mmol) in DCM (1.0 ml) was added TFA (105 μl, 1.361 mmol).The mixture was stirred for 1 h. The solvent was removed and the residuewas dissolved in DCM (1.0 ml). DIEA (29.7 μl, 0.170 mmol) was added toreaction vial, followed by 1 M acryloyl chloride (102 μl, 0.102 mmol).After stirring at 0° C. for 1 h, the solvent was removed and the residuewas diluted with methanol and purified with prep-LCMS to give thedesired product (25 mg, 81%). LC-MS calculated for C₁H₁₆BrClFN₂O₃(M+H)⁺: m/z=453.0, 455.0; found 453.1, 455.1.

Step 5.1-Acryloyl-9′-chloro-7′-fluoro-8′-(3-hydroxynaphthalen-1-yl)spiro[piperidine-4,2′-pyrano[3,2-c]quinolin]-4′(3′H)-one

A mixture of1-acryloyl-8′-bromo-9′-chloro-7′-fluorospiro[piperidine-4,2′-pyrano[3,2-c]quinolin]-4′(3′H)-one(36 mg, 0.079 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (47.2 mg,0.175 mmol), tetrakis (9.17 mg, 7.93 μmol) and sodium carbonate (25.2mg, 0.238 mmol) in 1,4-dioxane (1.0 mL)/water (0.200 mL) was stirred at90° C. for 2 h. The residue was dissolved in methanol and 1 N HCl andpurified with prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as a pair of atropisomers (brown solid, 28 mg, 68%).LC-MS calculated for C₂H₂₃ClFN₂O₄ (M+H)⁺: m/z=517.1; found 517.1.

Example 18.1-Acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-5′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one

Step 1. 1-(tert-Butyl) 3-methyl3-((7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)amino)-azetidine-1,3-dicarboxylate

This compound was prepared using similar procedures as described forExample 10, with 1-(tert-butyl) 3-methyl3-aminoazetidine-1,3-dicarboxylate replacing 1-(tert-butyl) 4-methyl4-aminopiperidine-1,4-dicarboxylate in Step 5. LC-MS calculated forC₁₉H₁₉BrCl₂FN₄O₆ (M+H)⁺: m/z=567.0, 569.0; found 567.0, 569.0.

Step 2. 1-(tert-Butyl) 3-methyl(S)-3-((7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-3-nitroquinolin-4-yl)amino)azetidine-1,3-dicarboxylate

This compound was prepared using similar procedures as described forExample 10, with 1-(tert-butyl) 3-methyl3-((7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)amino)-azetidine-1,3-dicarboxylatereplacing 1-(tert-butyl) 4-methyl4-((7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)amino)piperidine-1,4-dicarboxylatein Step 6. LC-MS calculated for C₂₅H₃₁BrClFN₅O₇ (M+H)⁺: m/z=646.1,648.1; found 646.1, 648.1.

Step 3. tert-Butyl(S)-8′-bromo-9′-chloro-7′-fluoro-5′-((1-methylpyrrolidin-2-yl)methoxy)-3′-oxo-3′,4′-dihydro-1′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 10, with 1-(tert-Butyl) 3-methyl(S)-3-((7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)-methoxy)-3-nitroquinolin-4-yl)amino)azetidine-1,3-dicarboxylatereplacing 1-(tert-butyl) 4-methyl(S)-4-((7-bromo-6-chloro-8-fluoro-2-((1-methylpyrrolidin-2-yl)methoxy)-3-nitroquinolin-4-yl)amino)piperidine-1,4-dicarboxylatein Step 7. LC-MS calculated for C₂₄H₂₉BrClFN₅O₄ (M+H)⁺: m/z=584.1,586.1; found 584.1, 586.1.

Step 4.(S)-1-Acryloyl-8′-bromo-9′-chloro-7′-fluoro-5′-((1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one

This compound was prepared using similar procedures as described forExample 10, with tert-butyl(S)-8′-bromo-9′-chloro-7′-fluoro-5′-((1-methylpyrrolidin-2-yl)methoxy)-3′-oxo-3′,4′-dihydro-1′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl(S)-8′-bromo-9′-chloro-7′-fluoro-5′-((1-methylpyrrolidin-2-yl)methoxy)-3′-oxo-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinoline]-1-carboxylatein Step 8. LC-MS calculated for C₂₂H₂₃BrClFN₅O₃ (M+H)⁺: m/z=538.1,540.1; found 538.1, 540.1.

Step 5.1-Acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-5′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one

This compound was prepared using similar procedures as described forExample 10, with(S)-1-acryloyl-8′-bromo-9′-chloro-7′-fluoro-5′-((1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-onereplacing(S)-1-acryloyl-8′-bromo-9′-chloro-7′-fluoro-5′-((1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-onein Step 9. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the product as a mixture ofdiastereomers as TFA salt. LC-MS calculated for C₂₈H₂₇ClF₂N₅O₄ (M+H)⁺:m/z=570.2; found 570.2. ¹H NMR (600 MHz, DMSO) b 8.23 (s, 2H), 7.32 (m,1H), 6.83 (d, J=8.3 Hz, 1H), 6.77 (m, 1H), 6.63 (bs, 1H), 6.38 (m, 1H),6.18 (d, J=16.9 Hz, 1H), 5.74 (dd, J=10.3, 2.0 Hz, 1H), 4.75 (t, J=9.4Hz, 1H), 4.50-4.45 (m, 2H), 4.33 (m, 1H), 4.25 (m, 1H), 4.12 (m, 1H),2.96 (m, 1H), 2.68 (m, 1H), 2.36 (s, 3H), 2.18 (m, 1H), 2.02 (m, 1H),1.68 (m, 3H).

Example 19a and Example 19b.4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-8′-methylspiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

Step 1. 1-(tert-Butyl) 3-methyl3-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylate

7-Bromo-2,4,6-trichloro-8-fluoro-3-nitroquinoline (Example 10, Step 4,210 mg, 0.561 mmol) and 1-(tert-butyl) 3-methylpiperidine-1,3-dicarboxylate (273 mg, 1.122 mmol) were combined and THF(4 ml) was added. The solution was cooled to −78° C. then LiHMDS (1.0 M,in THF, 785 μl, 0.785 mmol) was added. The mixture was stirred at −78°C. for 30 min, then allowed to warm up to room temperature. Afterquenching with saturated aqueous NH₄Cl, the mixture was diluted withEtOAc and separated. The aqueous layer was extracted with EtOAc and thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered and evaporated. The residue was purified with columnchromatography (DCM) to give the desired product as a solid.

Step 2. 1-(tert-butyl) 3-methyl3-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylate

To N,N-dimethylazetidin-3-amine dihydrochloride (0.104 g, 0.600 mmol) inMeCN was added DIPEA (0.35 ml, 2.00 mmol) and the reaction was stirredfor 10 min. Then 1-(tert-butyl) 3-methyl3-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylate(0.232 g, 0.400 mmol) was added. The mixture was stirred at roomtemperature for 30 min, then diluted with DCM. The resulting solutionwas washed with water, dried over Na₂SO₄, filtered and evaporated togive the desired product as a solid. The residue was used withoutfurther purification. LCMS calculated for C₂₆H₃₃BrClFN₅O₆ (M+H)⁺:m/z=644.1, 646.1; found 644.1, 646.1.

Step 3. tert-butyl7′-bromo-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

To a solution of 1-(tert-butyl) 3-methyl3-(7-bromo-6-chloro-2-(3-(dimethylamino)-azetidin-1-yl)-8-fluoro-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylate(0.100 g, 0.152 mmol) in acetic acid (2.0 ml) was added Fe (0.042 g,0.758 mmol). The resulting mixture was stirred at 80° C. for 30 min. Themixture was filtered through a pad of Celite and evaporated. The residuewas quenched with saturated aqueous NaHCO₃, diluted with DCM andseparated. The aqueous layer was extracted with DCM and the combinedorganic layer was washed with brine, dried over Na₂SO₄, filtered andevaporated. The residue was purified with column chromatography (0-20%MeOH in DCM) to give the desired product as a solid. LC-MS calculatedfor C₂₅H₃₁BrClFN₅O₃ (M+H)⁺: m/z=582.1, 584.1; found 582.1, 584.1.

Step 4. tert-butyl8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

A mixture of tert-butyl7′-bromo-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(0.050 g, 0.086 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (0.028 g,0.103 mmol), potassium phosphate (0.073 g, 0.343 mmol) and Pd(PPh₃)₄(0.020 mg, 0.017 mmol) was evacuated under vacuum and refilled withnitrogen (repeated three times). After addition of degassed 1,4-dioxane(0.4 ml) and water (0.04 ml), the reaction mixture was stirred at 100°C. for 2 h. The reaction mixture was cooled to room temperature,filtered through a pad of silica, washed with MeCN and evaporated. Theresidue was purified with column chromatography (0-20% MeOH in DCM) togive the desired product. LC-MS calculated for C₃₅H₃₈ClFN₅O₄ (M+H)⁺:m/z=646.3; found 646.2.

Step 5.4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-8′-methylspiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

A mixture of tert-butyl8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(0.030 g, 0.046 mmol), potassium methyltrifluoroborate (0.017 g, 0.139mmol), cesium carbonate (0.045 g, 0.139 mmol), palladium acetate (0.002g, 0.009 mmol) and di(1-adamantyl)-n-butylphosphine (0.007 g, 0.017mmol) was evacuated under vacuum and refilled with nitrogen (repeatedthree times). After addition of degassed toluene (0.42 ml) and water(0.04 ml), the reaction mixture was stirred at 120° C. for 1 h. Thereaction mixture was cooled to room temperature, filtered through a padof silica, washed with MeCN and evaporated. To the residue, DCM (1.0 ml)and TFA (1.2 ml, 15.5 mmol) were added. After stirring for 30 min atroom temperature, the volatiles were removed under reduced pressure. Theresidue was dissolved in MeCN, filtered and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired products as TFA salt.

Example 19a. Diastereomer 1. Peak 1. LC-MS calculated for C₃₁H₃₃FN₅O₂(M+H)⁺: m/z=526.3; found 526.3.

Example 19b. Diastereomer 2. Peak 2. LC-MS calculated for C₃₁H₃₃FN₅O₂(M+H)⁺: m/z=526.3; found 526.4.

Example 20a and Example 20b.8′-chloro-7′-(7-chloro-3-hydroxynaphthalen-1-yl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluorospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

A mixture of tert-butyl7′-bromo-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(Example 19a and 19b, Step 3, 0.050 g, 0.086 mmol),6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol(0.031 g, 0.103 mmol), potassium phosphate (0.073 g, 0.343 mmol) andPd(PPh₃)₄ (0.020 mg, 0.017 mmol) was evacuated under vacuum and refilledwith nitrogen (repeated three times). After addition of degassed1,4-dioxane (0.4 ml) and water (0.04 ml), the reaction mixture wasstirred at 100° C. for 2 h. The reaction mixture was cooled to roomtemperature and filtered through a pad of silica, washed with MeCN andevaporated. To the residue, DCM (1.0 ml) and TFA (1.2 ml, 15.5 mmol)were added. After stirring for 30 min at room temperature, the volatileswere removed under reduced pressure. The residue was dissolved in MeCN,filtered and purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired products as TFA salt.

Example 20a. Diastereomer 1. Peak 1. LC-MS calculated for C₃₀H₂₉Cl₂FN₅O₂(M+H)⁺: m/z=580.2; found 580.2.

Example 20b. Diastereomer 2. Peak 2. LC-MS calculated for C₃₀H₂₉Cl₂FN₅O₂(M+H)⁺: m/z=580.2; found 580.2.

Example 21a and Example 21b.8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

Step 1. 2-(tert-butyl) 5-methyl5-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)-2-azabicyclo[2.2.1]heptane-2,5-dicarboxylate

This compound was prepared using similar procedures as described forExample 19a and 19b, with 2-(tert-butyl) 5-methyl2-azabicyclo[2.2.1]heptane-2,5-dicarboxylate replacing 1-(tert-butyl)3-methyl piperidine-1,3-dicarboxylate in Step 1.

Step 2. 2-(tert-butyl) 5-methyl5-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-3-nitroquinolin-4-yl)-2-azabicyclo[2.2.1]heptane-2,5-dicarboxylate

This compound was prepared using similar procedures as described forExample 19a and 19b, with 2-(tert-butyl) 5-methyl5-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)-2-azabicyclo[2.2.1]heptane-2,5-dicarboxylatereplacing 1-(tert-Butyl) 3-methyl3-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatein Step 2. LC-MS calculated for C₂₇H₃₃BrClFN₅O₆ (M+H)⁺: m/z=656.1,658.1; found 656.1, 658.0.

Step 3. tert-butyl7′-bromo-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydro-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-pyrrolo[2,3-c]quinoline]-5-carboxylate

This compound was prepared using similar procedures as described forExample 19a and 19b, with 2-(tert-butyl) 5-methyl5-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-3-nitroquinolin-4-yl)-2-azabicyclo[2.2.1]heptane-2,5-dicarboxylatereplacing 1-(tert-butyl) 3-methyl3-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatein Step 3. LC-MS calculated for C₂₆H₃₁BrClFN₅O₃ (M+H)⁺: m/z=594.1,596.1; found 594.1, 596.1.

Step 4.8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

A mixture of tert-butyl7′-bromo-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydro-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-pyrrolo[2,3-c]quinoline]-5-carboxylate(0.059 g, 0.099 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-ol (0.040 g,0.149 mmol), potassium phosphate (0.084 g, 0.397 mmol) and Pd(PPh₃)₄(0.022 mg, 0.020 mmol) was evacuated under vacuum and refilled withnitrogen (repeated three times). After addition of degassed 1,4-dioxane(0.5 ml) and water (0.05 ml), the reaction mixture was stirred at 100°C. for 2 h. The reaction mixture was cooled to room temperature,filtered through a pad of silica, washed with MeCN and evaporated. Tothe residue, DCM (1.0 ml) and TFA (1.2 ml, 15.5 mmol) were added. Afterstirring for 30 min at room temperature, the volatiles were removedunder reduced pressure. The residue was dissolved in MeCN, filtered andpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproducts as TFA salt.

Example 21a. Diastereomer 1. Peak 1. LC-MS calculated for C₃₁H₃₀ClFN₅O₂(M+H)⁺: m/z=558.2; found 558.2.

Example 21b. Diastereomer 2. Peak 2. LC-MS calculated for C₃₁H₃₀ClFN₅O₂(M+H)⁺: m/z=558.2; found 558.2.

Example 22.3-amino-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)spiro[cyclobutane-1,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

Step 1. methyl1-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate

This compound was prepared using similar procedures as described forExample 19a and 19b, with methyl3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate replacing1-(tert-butyl) 3-methyl piperidine-1,3-dicarboxylate in Step 1.

Step 2. methyl1-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-3-nitroquinolin-4-yl)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylate

This compound was prepared using similar procedures as described forExample 19a and 19b, with methyl1-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylatereplacing 1-(tert-Butyl) 3-methyl3-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatein Step 2. LC-MS calculated for C₂₅H₃₁BrClFN₅O₆ (M+H)⁺: m/z=630.1,632.1; found 630.1, 632.1.

Step 3. tert-butyl(7′-bromo-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[cyclobutane-1,1′-pyrrolo[2,3-c]quinolin]-3-yl)carbamate

This compound was prepared using similar procedures as described forExample 19a and 19b, with methyl1-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-3-nitroquinolin-4-yl)-3-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylatereplacing 1-(tert-butyl) 3-methyl3-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatein Step 3. LC-MS calculated for C₂₄H₂₉BrClFN₅O₃ (M+H)⁺: m/z=568.1,570.1; found 568.2, 570.3.

Step 4.3-amino-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)spiro[cyclobutane-1,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

This compound was prepared using similar procedures as described forExample 19a and 19b, with tert-butyl(7′-bromo-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[cyclobutane-1,1′-pyrrolo[2,3-c]quinolin]-3-yl)carbamatereplacing tert-butyl7′-bromo-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatein Step 4. The residue was dissolved in MeCN, filtered and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt. LC-MS calculated for C₂₉H₂₈ClFN₅O₂ (M+H)⁺: m/z=532.2; found532.2.

Example 23a and Example 23b.4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

Step 1. 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid

1-iodopyrrolidine-2,5-dione (21.5 g, 95.0 mmol) was added to a DMF (200ml) solution of 2-amino-4-bromo-3-fluorobenzoic acid (20.3 g, 87.0mmol)) and then the reaction was stirred at 80° C. for 3 h. The mixturewas cooled with ice water and then water (500 mL) was added, theprecipitation was filtered and washed with water, dried under reducedpressure to provide the desired product as a solid.

Step 2. 7-bromo-8-fluoro-6-iodo-2H-benzo[d][1,3]oxazine-2,4(1H)-dione

Triphosgene (11.5 g, 38.9 mmol) was added to a dioxane (200 ml) solutionof 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (28.0 g, 78.0 mmol) andthen the reaction was stirred at 80° C. for 2 h. The reaction mixturewas cooled with ice water and then filtered. The solid was washed withethyl acetate to provide the desired product as a solid.

Step 3. 7-bromo-8-fluoro-6-iodo-3-nitroquinoline-2,4-diol

N,N-Diisopropyl ethylamine (17.1 ml, 98.0 mmol) was added to a toluene(200 ml) solution of ethyl 2-nitroacetate (10.9 ml, 98.0 mmol) and7-bromo-8-fluoro-6-iodo-2H-benzo[d][1,3]oxazine-2,4(1H)-dione (19.0 g,49.0 mmol) and then the reaction was stirred at 95° C. for 3 h. Thereaction mixture was cooled with ice water and then filtered. The solidwas washed with hexanes to provide the desired product as a solid. LC-MScalculated for C₉H₄BrFIN₂O₄ (M+H)⁺: m/z=428.8, 430.8; found 429.0,431.0.

Step 4. 7-bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline

N,N-Diisopropyl ethylamine (4.9 ml, 28.0 mmol) was added to a mixture of7-bromo-8-fluoro-6-iodo-3-nitroquinoline-2,4-diol (6.00 g, 14.0 mmol) inphosphorus oxychloride (6.5 ml, 70.0 mmol) and then the reaction wasstirred at 100° C. for 2 h. The solvent was removed under reducedpressure and then azeotroped with toluene 3 times. The residue waspurified with column chromatography (DCM) to give the desired product asa solid.

Step 5. 1-(tert-butyl) 3-methyl3-(7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylate

This compound was prepared using similar procedures as described forExample 19a and 19b, with7-bromo-2,4-dichloro-8-fluoro-6-iodo-3-nitroquinoline replacing7-Bromo-2,4,6-trichloro-8-fluoro-3-nitroquinoline in Step 1.

Step 6. 1-(tert-butyl) 3-methyl3-(7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodo-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylate

This compound was prepared using similar procedures as described forExample 19a and 19b, with 1-(tert-butyl) 3-methyl3-(7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatereplacing 1-(tert-butyl) 3-methyl3-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatein Step 2. LC-MS calculated for C₂₆H₃₃BrFIN₅O₆ (M+H)⁺: m/z=736.1, 738.1;found 736.1, 738.0.

Step 7. tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 19a and 19b, with 1-(tert-butyl) 3-methyl3-(7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodo-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatereplacing 1-(tert-butyl) 3-methyl3-(7-bromo-6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatein Step 3. LC-MS calculated for C₂₅H₃₁BrFIN₅O₃ (M+H)⁺: m/z=674.1, 676.1;found 674.1, 676.0.

Step 8. tert-butyl7′-bromo-8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

A mixture of tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(0.133 g, 0.197 mmol) and bis(triphenylphosphine)palladium dichloride(0.014 g, 0.020 mmol) was evacuated under vacuum and refilled withnitrogen (repeated three times). After addition of a 0.5 M THF solutionof (3-cyanopropyl)zinc bromide (2.0 ml, 0.986 mmol), the reactionmixture was stirred at 50° C. for 30 min. After cooling to roomtemperature, the mixture was quenched with saturated aqueous NH₄Cl,diluted with EtOAc and separated. The aqueous layer was extracted withEtOAc and the combined organic layer was washed with brine, dried overNa₂SO₄, filtered and evaporated. The residue was purified with columnchromatography (0-20% MeOH in DCM) to give the desired product. LC-MScalculated for C₂₉H₃₇BrFN₆O₃ (M+H)⁺: m/z=615.2, 617.2; found 615.2,617.2.

Step 9.4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

This compound was prepared using similar procedures as described forExample 21a and 21b, with tert-butyl7′-bromo-8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl7′-bromo-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydro-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-pyrrolo[2,3-c]quinoline]-5-carboxylatein Step 4. The residue was dissolved in MeCN, filtered and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asTFA salt.

Example 23a. Diastereomer 1. Peak 1. LC-MS calculated for C₃₄H₃₆FN₆O₂(M+H)⁺: m/z=579.3; found 579.3.

Example 23b. Diastereomer 2. Peak 2. LC-MS calculated for C₃₄H₃₆FN₆O₂(M+H)⁺: m/z=579.3; found 579.3.

Example 24a and Example 24b.2-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)acetonitrile

Step 1. tert-butyl7′-bromo-8′-(cyanomethyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

A mixture of tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(Example 23a and 23b, Step 7, 0.100 g, 0.148 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.032 g, 0.163mmol), potassium phosphate (0.126 g, 0.593 mmol) and Pd(PPh₃)₄ (0.017mg, 0.015 mmol) was evacuated under vacuum and refilled with nitrogen(repeated three times). After addition of degassed 1,4-dioxane (0.7 ml)and water (0.07 ml), the reaction mixture was stirred at 100° C. for 2h. After cooling to room temperature, the mixture was added water,diluted with DCM and separated. The aqueous layer was extracted with DCMand the combined organic layer was washed with water, dried over Na₂SO₄,filtered and evaporated. The residue was purified with columnchromatography (0-20% MeOH in DCM) to give the desired product. LC-MScalculated for C₂₇H₃₃BrFN₆O₃ (M+H)⁺: m/z=587.2, 589.2; found 587.1,589.2.

Step 2.2-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)acetonitrile

This compound was prepared using similar procedures as described forExample 21a and 21b, with tert-butyl7′-bromo-8′-(cyanomethyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl7′-bromo-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydro-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-pyrrolo[2,3-c]quinoline]-5-carboxylatein Step 4. The residue was dissolved in MeCN, filtered and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired products asTFA salt.

Example 24a. Diastereomer 1. Peak 1. LC-MS calculated for C₃₂H₃₂FN₆O₂(M+H)⁺: m/z=551.3; found 551.3.

Example 24b. Diastereomer 2. Peak 2. LC-MS calculated for C₃₂H₃₂FN₆O₂(M+H)⁺: m/z=551.3; found 551.3.

Example 25a and Example 25b.3-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)propanenitrile

Step 1. tert-butyl(E)-7′-bromo-8′-(2-cyanovinyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

A mixture of tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(Example 23a and 23b, Step 7, 0.150 g, 0.222 mmol), palladium acetate(0.005 g, 0.022 mmol), tri-o-tolylphosphane (0.014 g, 0.044 mmol) wasevacuated under vacuum and refilled with nitrogen (repeated threetimes). After addition of degassed DMF (1.1 ml), triethylamine (0.046ml, 0.334 mmol) and acrylonitrile (0.029 ml, 0.445 mmol), the reactionmixture was stirred at 80° C. for 3 h. After cooling to roomtemperature, the mixture was added water, diluted with DCM andseparated. The aqueous layer was extracted with DCM and the combinedorganic layer was washed with water, dried over Na₂SO₄, filtered andevaporated. The residue was purified with column chromatography (0-20%MeOH in DCM) to give the desired product. LC-MS calculated forC₂₈H₃₃BrFN₆O₃ (M+H)⁺: m/z=599.2, 601.2; found 599.1, 601.2.

Step 2. tert-butyl(E)-8′-(2-cyanovinyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-(methoxymethoxy)naphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

A mixture of tert-butyl(E)-7′-bromo-8′-(2-cyanovinyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(0.120 g, 0.200 mmol),2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0.079 g, 0.250 mmol), potassium phosphate (0.170 g, 0.800 mmol) andPd(PPh₃)₄ (0.035 g, 0.030 mmol) was evacuated under vacuum and refilledwith nitrogen (repeated three times). After addition of degassed1,4-dioxane (0.9 ml) and water (0.09 ml), the reaction mixture wasstirred at 100° C. for 2 h. The reaction mixture was cooled to roomtemperature, filtered through a pad of silica, washed with MeCN andevaporated. The residue was purified with column chromatography (0-20%MeOH in DCM) to give the desired product. LC-MS calculated forC₄₀H₄₄FN₆O₅ (M+H)⁺: m/z=707.3; found 707.3.

Step 3.3-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)propanenitrile

To an anhydrous THF solution of tert-butyl(E)-8′-(2-cyanovinyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-(methoxymethoxy)naphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(0.100 g, 0.141 mmol) cooled to 0° C. was added 1.0 M THF solution oflithium triethylborohydride (0.85 ml, 0.850 mmol). After stirring for 30min, the reaction was quenched with saturated aqueous NH₄Cl, dilutedwith EtOAc and separated. The aqueous layer was extracted with EtOAc andthe combined organic layer was washed with brine, dried over Na₂SO₄,filtered and evaporated. To the residue, DCM (1.0 ml) and TFA (1.2 ml,15.5 mmol) were added. After stirring for 30 min at room temperature,water (0.2 ml) was added and the reaction stirred for another 10 min.Then the volatiles were removed under reduced pressure. The residue wasdissolved in MeCN, filtered and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired products as TFA salt.

Example 25a. Diastereomer 1. Peak 1. LC-MS calculated for C₃₃H₃₄FN₆O₂(M+H)⁺: m/z=565.3; found 565.3.

Example 25b. Diastereomer 2. Peak 2. LC-MS calculated for C₃₃H₃₄FN₆O₂(M+H)⁺: m/z=565.3; found 565.3.

Example 26a and Example 26b.8′-(2-chlorobenzyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)spiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

Step 1. tert-butyl7′-bromo-8′-(2-chlorobenzyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with (2-chlorobenzyl)zinc chloride replacing(3-cyanopropyl)zinc bromide in Step 8. LC-MS calculated forC₃₂H₃₇BrClFN₅O₃ (M+H)⁺: m/z=672.2, 674.2; found 672.2, 674.2.

Step 2.8′-(2-chlorobenzyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)spiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one

This compound was prepared using similar procedures as described forExample 21a and 21b, with tert-butyl7′-bromo-8′-(2-chlorobenzyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl7′-bromo-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydro-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-pyrrolo[2,3-c]quinoline]-5-carboxylatein Step 4. The residue was dissolved in MeCN, filtered and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired products asTFA salt.

Example 26a. Diastereomer 1. Peak 1. LC-MS calculated for C₃₇H₃₆ClFN₅O₂(M+H)⁺: m/z=636.3; found 636.3.

Example 26b. Diastereomer 2. Peak 2. LC-MS calculated for C₃₇H₃₆ClFN₅O₂(M+H)⁺: m/z=636.3; found 636.3.

Example 27a and Example 27b.2-((4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)methyl)benzonitrile

Step 1. tert-butyl7′-bromo-8′-(2-cyanobenzyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with (2-cyanobenzyl)zinc bromide replacing(3-cyanopropyl)zinc bromide in Step 8. LC-MS calculated forC₃₃H₃₇BrFN₆O₃ (M+H)⁺: m/z=663.2, 665.2; found 663.2, 665.2.

Step 2.2-((4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)methyl)benzonitrile

This compound was prepared using similar procedures as described forExample 21a and 21b, with tert-butyl7′-bromo-8′-(2-cyanobenzyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl7′-bromo-8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydro-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-pyrrolo[2,3-c]quinoline]-5-carboxylatein Step 4. The residue was dissolved in MeCN, filtered and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired products asTFA salt.

Example 27a. Diastereomer 1. Peak 1. LC-MS calculated for C₃₈H₃₆FN₆O₂(M+H)⁺: m/z=627.3; found 627.1.

Example 27b. Diastereomer 2. Peak 2. LC-MS calculated for C₃₈H₃₆FN₆O₂(M+H)⁺: m/z=627.3; found 627.1.

Example 28a and Example 28b.4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

Step 1. tert-butyl8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-(methoxymethoxy)naphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

A mixture of tert-butyl7′-bromo-8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(Example 23a and 23b, Step 8, 0.310 g, 0.504 mmol),2-(3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(0198 g, 0.630 mmol), potassium phosphate (0.428 g, 2.01 mmol) andPd(PPh₃)₄ (0.087 g, 0.076 mmol) was evacuated under vacuum and refilledwith nitrogen (repeated three times). After addition of degassed1,4-dioxane (2.3 ml) and water (0.23 ml), the reaction mixture wasstirred at 100° C. for 2 h. The reaction mixture was cooled to roomtemperature, filtered through a pad of silica, washed with MeCN andevaporated. The residue was purified with column chromatography (0-20%MeOH in DCM) to give the desired product. LC-MS calculated forC₄₁H₄₈FN₆O₅ (M+H)⁺: m/z=723.4; found 723.3.

Step 2. di-tert-butyl8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-(methoxymethoxy)naphthalen-1-yl)-2′-oxospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1,3′(2′H)-dicarboxylate

To a THF solution of tert-butyl8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-(methoxymethoxy)naphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(0.270 g, 0.374 mmol) was added di-tert-butyl carbonate (0.13 ml, 0.560mmol), triethylamine (0.15 ml, 1.12 mmol) andN,N-dimethylpyridin-4-amine (0.005 g, 0.037 mmol). The reaction wasstirred for 1 h, diluted with EtOAc, washed with water, dried overNa₂SO₄, filtered and evaporated. The resulting yellow solids were usedwithout further purification for the next step. LC-MS calculated forC₄₆H₅₆FN₆O₇ (M+H)⁺: m/z=823.4; found 823.3.

Step 3. di-tert-butyl8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-hydroxy-7′-(3-(methoxymethoxy)naphthalen-1-yl)spiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1,3′(2′H)-dicarboxylate

To a MeOH solution containing di-tert-butyl8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-(methoxymethoxy)naphthalen-1-yl)-2′-oxospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1,3′(2′H)-dicarboxylate(0.080 g, 0.097 mmol) cooled to 0° C. was added sodium borohydride(0.018 g, 0.486 mmol) in batches. After stirring for 15 min, thereaction was quenched with saturated aqueous NH₄Cl, diluted with EtOAcand separated. The aqueous layer was extracted with EtOAc and thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered and evaporated. The residue was purified with columnchromatography (0-20% MeOH in DCM) to give the desired product. LC-MScalculated for C₄₆H₅₈FN₆O₇ (M+H)⁺: m/z=825.4; found 825.6.

Step 4.4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

To a 1,4-dioxane solution containing di-tert-butyl8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-hydroxy-7′-(3-(methoxymethoxy)naphthalen-1-yl)spiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1,3′(2′H)-dicarboxylate(0.060 g, 0.073 mmol) was added potassium phosphate (0.077 g, 0.365mmol). After stirring at 100° C. for 16 h, the mixture was filteredthrough a pad of Celite, dried over Na₂SO₄, and evaporated. The residuewas dissolved in anhydrous THF, cooled to 0° C. and added a 1.0 M THFsolution of lithium triethylborohydride (0.37 ml, 0.365 mmol). Afterstirring for 30 min, the reaction was quenched with saturated aqueousNH₄Cl, diluted with EtOAc and separated. The aqueous layer was extractedwith EtOAc and the combined organic layer was washed with brine, driedover Na₂SO₄, filtered and evaporated. To the residue, DCM (1.0 ml) andTFA (1.2 ml, 15.5 mmol) were added. After stirring for 30 min at roomtemperature, water (0.2 ml) was added and the reaction stirred foranother 10 min. Then the volatiles were removed under reduced pressure.The residue was dissolved in MeCN, filtered and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired products as TFA salt.

Example 28a. Diastereomer 1. Peak 1. LC-MS calculated for C₃₄H₃₈FN₆O(M+H)⁺: m/z=565.3; found 565.4.

Example 28b. Diastereomer 2. Peak 2. LC-MS calculated for C₃₄H₃₈FN₆O(M+H)⁺: m/z=565.3; found 565.4. ¹H NMR (500 MHz, DMSO) b 9.25 (br), 8.60(br), 7.79 (d, 1H, J=8.3 Hz), 7.72 (s, 1H), 7.44-7.39 (m, 1H), 7.24 (d,1H, J=2.2 Hz), 7.20-7.13 (m, 2H), 7.03 (d, 1H, J=2.4 Hz), 4.50-4.27 (m,5H), 3.95-3.50 (m, 4H), 3.37 (m, 2H), 2.83 (s, 6H), 2.66-2.55 (m, 2H),2.26 (t, 2H, J=7.2 Hz), 1.92 (m, 4H), 1.54 (m, 2H).

Example 29.3-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[azetidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)propanenitrile

Step 1. 1-(tert-butyl) 3-methyl3-(7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)azetidine-1,3-dicarboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with 1-(tert-butyl) 3-methylazetidine-1,3-dicarboxylate replacing 1-(tert-butyl) 3-methylpiperidine-1,3-dicarboxylate in Step 5.

Step 2. 1-(tert-butyl) 3-methyl3-(7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodo-3-nitroquinolin-4-yl)azetidine-1,3-dicarboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with 1-(tert-butyl) 3-methyl3-(7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)azetidine-1,3-dicarboxylatereplacing 1-(tert-butyl) 3-methyl3-(7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatein Step 6. LC-MS calculated for C₂₄H₂₉BrFIN₅O₆ (M+H)⁺: m/z=708.0, 710.0;found 708.0, 710.0.

Step 3. tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[azetidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with 1-(tert-butyl) 3-methyl3-(7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodo-3-nitroquinolin-4-yl)azetidine-1,3-dicarboxylatereplacing 1-(tert-butyl) 3-methyl3-(7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodo-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatein Step 7. LC-MS calculated for C₂₃H₂₇BrFIN₅O₃ (M+H)⁺: m/z=646.0, 648.0;found 646.0, 648.0.

Step 4. tert-butyl(E)-7′-bromo-8′-(2-cyanovinyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[azetidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 25a and 25b, with tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[azetidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatein Step 1. LC-MS calculated for C₂₆H₂₉BrFN₆O₃ (M+H)⁺: m/z=571.1, 573.1;found 571.1, 573.1.

Step 5. tert-butyl(E)-8′-(2-cyanovinyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-(methoxymethoxy)naphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[azetidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 25a and 25b, with tert-butyl(E)-7′-bromo-8′-(2-cyanovinyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[azetidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl(E)-7′-bromo-8′-(2-cyanovinyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatein Step 2. LC-MS calculated for C₃₈H₄₀FN₆O₅ (M+H)⁺: m/z=679.3; found679.3.

Step 6.3-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[azetidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)propanenitrile

This compound was prepared using similar procedures as described forExample 25a and 25b, with tert-butyl(E)-8′-(2-cyanovinyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-(methoxymethoxy)naphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[azetidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl(E)-8′-(2-cyanovinyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-(methoxymethoxy)naphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatein Step 3. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired products as TFA salt. LC-MScalculated for C₃₁H₃₀FN₆O₂ (M+H)⁺: m/z=537.2; found 537.3.

Example 30a and Example 30b.4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[pyrrolidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

Step 1. 1-(tert-butyl) 3-methyl3-(7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)pyrrolidine-1,3-dicarboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with 1-(tert-butyl) 3-methylpyrrolidine-1,3-dicarboxylate replacing 1-(tert-butyl) 3-methylpiperidine-1,3-dicarboxylate in Step 5.

Step 2. 1-(tert-butyl) 3-methyl3-(7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodo-3-nitroquinolin-4-yl)pyrrolidine-1,3-dicarboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with 1-(tert-butyl) 3-methyl3-(7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)pyrrolidine-1,3-dicarboxylatereplacing 1-(tert-butyl) 3-methyl3-(7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatein Step 6. LC-MS calculated for C₂₅H₃₁BrFIN₅O₆ (M+H)⁺: m/z=722.0, 724.0;found 722.0, 724.0.

Step 3. tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[pyrrolidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with 1-(tert-butyl) 3-methyl3-(7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodo-3-nitroquinolin-4-yl)pyrrolidine-1,3-dicarboxylatereplacing 1-(tert-butyl) 3-methyl3-(7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodo-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatein Step 7. LC-MS calculated for C₂₄H₂₉BrFIN₅O₃ (M+H)⁺: m/z=660.0, 662.0;found 660.0, 662.1.

Step 4. tert-butyl7′-bromo-8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[pyrrolidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[pyrrolidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatein Step 8. LC-MS calculated for C₂₈H₃₅BrFN₆O₃ (M+H)⁺: m/z=601.2, 603.2;found 601.2, 603.2.

Step 5.4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[pyrrolidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

This compound was prepared using similar procedures as described forExample 23a and 23b, with tert-butyl7′-bromo-8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[pyrrolidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl7′-bromo-8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatein Step 9. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired products as TFA salt.

Example 30a. Diastereomer 1. Peak 1. LC-MS calculated for C₃₃H₃₄FN₆O₂(M+H)⁺: m/z=565.3; found 565.4.

Example 30b. Diastereomer 2. Peak 2. LC-MS calculated for C₃₃H₃₄FN₆O₂(M+H)⁺: m/z=565.3; found 565.4.

Example 31a and Example 31b.4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[morpholine-2,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

Step 1. 4-(tert-butyl) 2-methyl2-(7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)morpholine-2,4-dicarboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with 4-(tert-butyl) 2-methylmorpholine-2,4-dicarboxylate replacing 1-(tert-butyl) 3-methylpiperidine-1,3-dicarboxylate in Step 5.

Step 2. 4-(tert-butyl) 2-methyl2-(7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodo-3-nitroquinolin-4-yl)morpholine-2,4-dicarboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with 4-(tert-butyl) 2-methyl2-(7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)morpholine-2,4-dicarboxylatereplacing 1-(tert-butyl) 3-methyl3-(7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatein Step 6. LC-MS calculated for C₂₅H₃₁BrFIN₅O₇ (M+H)⁺: m/z=738.0, 740.0;found 738.0, 740.0.

Step 3. tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[morpholine-2,1′-pyrrolo[2,3-c]quinoline]-4-carboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with 4-(tert-butyl) 2-methyl2-(7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodo-3-nitroquinolin-4-yl)morpholine-2,4-dicarboxylatereplacing 1-(tert-butyl) 3-methyl3-(7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodo-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatein Step 7. LC-MS calculated for C₂₄H₂₉BrFIN₅O₄ (M+H)⁺: m/z=676.0, 678.0;found 676.0, 678.0.

Step 4. tert-butyl7′-bromo-8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[morpholine-2,1′-pyrrolo[2,3-c]quinoline]-4-carboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[morpholine-2,1′-pyrrolo[2,3-c]quinoline]-4-carboxylatereplacing tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatein Step 8. LC-MS calculated for C₂₈H₃₅BrFN₆O₄ (M+H)⁺: m/z=617.2, 619.2;found 617.2, 619.2.

Step 5.4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[morpholine-2,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

This compound was prepared using similar procedures as described forExample 23a and 23b, with tert-butyl7′-bromo-8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[morpholine-2,1′-pyrrolo[2,3-c]quinoline]-4-carboxylatereplacing tert-butyl7′-bromo-8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatein Step 9. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired products as TFA salt.

Example 31a. Diastereomer 1. Peak 1. LC-MS calculated for C₃₃H₃₄FN₆O₃(M+H)⁺: m/z=581.3; found 581.4.

Example 31b. Diastereomer 2. Peak 2. LC-MS calculated for C₃₃H₃₄FN₆O₃(M+H)⁺: m/z=581.3; found 581.3.

Example 32a, Example 32b and Example 32c.4-(6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

Step 1. 1-(tert-butyl) 3-methyl3-(7-bromo-8-fluoro-6-iodo-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylate

This compound was prepared using similar procedures as described forExample 10, with 1-(tert-butyl) 3-methyl3-(7-bromo-2-chloro-8-fluoro-6-iodo-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylate(Example 23a and 23b, Step 5) replacing 1-(tert-butyl) 4-methyl4-((7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)amino)piperidine-1,4-dicarboxylatein Step 6. LC-MS calculated for C₂₇H₃₄BrFIN₄O₇ (M+H)⁺: m/z=751.1, 753.1;found 751.0, 753.0.

Step 2. tert-butyl7′-bromo-6′-fluoro-8′-iodo-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with 1-(tert-butyl) 3-methyl3-(7-bromo-8-fluoro-6-iodo-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatereplacing 1-(tert-butyl) 3-methyl3-(7-bromo-2-(3-(dimethylamino)azetidin-1-yl)-8-fluoro-6-iodo-3-nitroquinolin-4-yl)piperidine-1,3-dicarboxylatein Step 6. LC-MS calculated for C₂₆H₃₂BrFIN₄O₄ (M+H)⁺: m/z=689.1, 691.1;found 689.0, 691.1.

Step 3. tert-butyl7′-bromo-8′-(3-cyanopropyl)-6′-fluoro-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 23a and 23b, with tert-butyl7′-bromo-6′-fluoro-8′-iodo-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl7′-bromo-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-8′-iodo-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatein Step 8. LC-MS calculated for C₃₀H₃₈BrFN₅O₄ (M+H)⁺: m/z=630.2, 633.2;found 630.2, 633.2.

Step 4.4-(6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

This compound was prepared using similar procedures as described forExample 23a and 23b, with tert-butyl7′-bromo-8′-(3-cyanopropyl)-6′-fluoro-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatereplacing tert-butyl7′-bromo-8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatein Step 9. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired products as TFA salt.

Example 32a. Peak 1. LC-MS calculated for C₃₅H₃₇FN₅O₃ (M+H)⁺: m/z=594.3;found 594.5.

Example 32b. Peak 2. LC-MS calculated for C₃₅H₃₇FN₅O₃ (M+H)⁺: m/z=594.3;found 594.5.

Example 32c. Peak 3. LC-MS calculated for C₃₅H₃₇FN₅O₃ (M+H)⁺: m/z=594.3;found 594.5.

Example 33a, Example 33b and Example 33c.4-(6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-3′-methyl-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

Step 1. tert-butyl8′-(3-cyanopropyl)-6′-fluoro-7′-(3-(methoxymethoxy)naphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate

This compound was prepared using similar procedures as described forExample 28a and 28b, with tert-butyl7′-bromo-8′-(3-cyanopropyl)-6′-fluoro-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(Example 32a, 32b, 32c, Step 3) replacing tert-butyl7′-bromo-8′-(3-cyanopropyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylatein Step 1. LC-MS calculated for C₄₂H₄₉FN₅O₆ (M+H)⁺: m/z=738.4; found738.6.

Step 2.4-(6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-3′-methyl-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

To a MeCN solution containing tert-butyl8′-(3-cyanopropyl)-6′-fluoro-7′-(3-(methoxymethoxy)naphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(0.050 g, 0.068 mmol) was added cesium carbonate (0.044 g, 0.136 mmol)and 2.0 M tert-butyl methyl ether solution of iodomethane (0.041 ml,0.082 mmol). The reaction was stirred at 60° C. for 1 h. Then thereaction mixture was filtered through a pad of Celite, diluted withwater and DCM and separated. The organic layer was dried over Na₂SO₄,filtered and evaporated. To the residue, DCM (1.0 ml) and TFA (1.2 ml,15.5 mmol) were added. After stirring for 30 min at room temperature,water (0.2 ml) was added and the reaction stirred for another 10 min.Then the volatiles were removed under reduced pressure. The residue wasdissolved in MeCN, filtered and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired products as TFA salt.

Example 33a. Peak 1. LC-MS calculated for C₃₋₆H₃₉FN₅O₃ (M+H)⁺:m/z=608.3; found 608.4.

Example 33b. Peak 2. LC-MS calculated for C₃₋₆H₃₉FN₅O₃ (M+H)⁺:m/z=608.3; found 608.4.

Example 33c. Peak 3. LC-MS calculated for C₃₋₆H₃₉FN₅O₃ (M+H)⁺:m/z=608.3; found 608.4.

Example 34a, Example 34b and Example 34c.4-(6′-fluoro-3′-(2-hydroxyethyl)-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

To a MeCN solution containing tert-butyl8′-(3-cyanopropyl)-6′-fluoro-7′-(3-(methoxymethoxy)naphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinoline]-1-carboxylate(Example 33a, 33b and 33c, Step 1, 0.050 g, 0.068 mmol) was added cesiumcarbonate (0.044 g, 0.136 mmol) and(2-bromoethoxy)(tert-butyl)dimethylsilane (0.029 ml, 0.136 mmol). Thereaction was stirred at 60° C. for 1 h. Then the reaction mixture wasfiltered through a pad of Celite, diluted with water and DCM andseparated. The organic layer was dried over Na₂SO₄, filtered andevaporated. The residue was dissolved in anhydrous THF and added 1.0 MTHF solution of tetrabutylammonium fluoride (0.10 ml, 0.102 mmol). Afterstirring for 30 min, the reaction mixture was filtered through a pad ofCelite, diluted with water and EtOAc and separated. The organic layerwas dried over Na₂SO₄, filtered and evaporated. To the residue, DCM (1.0ml) and TFA (1.2 ml, 15.5 mmol) were added. After stirring for 30 min atroom temperature, water (0.2 ml) was added and the reaction stirred foranother 10 min. Then the volatiles were removed under reduced pressure.The residue was dissolved in MeCN, filtered and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired products as TFA salt.

Example 34a. Peak 1. LC-MS calculated for C₃₇H₄₁FN₅O₄ (M+H)⁺: m/z=638.3;found 638.5.

Example 34b. Peak 2. LC-MS calculated for C₃₇H₄₁FN₅O₄ (M+H)⁺: m/z=638.3;found 638.5.

Example 34c. Peak 3. LC-MS calculated for C₃₇H₄₁FN₅O₄ (M+H)⁺: m/z=638.3;found 638.5.

Example 35a, Example 35b and Example 35c.4-(6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-3′-isopentyl-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

This compound was prepared using similar procedures as described forExample 33a, 33b and 33c, with 1-bromo-3-methylbutane replacingiodomethane in Step 2. The reaction mixture was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired products as TFA salt.

Example 35a. Peak 1. LC-MS calculated for C₄₀H₄₇FN₅O₃ (M+H)⁺: m/z=664.4;found 664.6.

Example 35b. Peak 2. LC-MS calculated for C₄₀H₄₇FN₆O₃ (M+H)⁺: m/z=664.4;found 664.6.

Example 35c. Peak 3. LC-MS calculated for C₄₀H₄₇FN₅O₃ (M+H)⁺: m/z=664.4;found 664.6.

Example 36a, Example 36b and Example 36c.4-(3′-(cyanomethyl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile

This compound was prepared using similar procedures as described forExample 33a, 33b and 33c, with 2-bromoacetonitrile replacing iodomethanein Step 2. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired products as TFA salt.

Example 36a. Peak 1. LC-MS calculated for C₃₇H₃₈FN₆O₃ (M+H)⁺: m/z=633.3;found 633.3.

Example 36b. Peak 2. LC-MS calculated for C₃₇H₃₈FN₆O₃ (M+H)⁺: m/z=633.3;found 633.3.

Example 36c. Peak 3. LC-MS calculated for C₃₇H₃₈FN₆O₃ (M+H)⁺: m/z=633.3;found 633.3.

Example 37a, Example 37b and Example 37c.2-(8′-(3-cyanopropyl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-3′(2′H)-yl)acetamide

This compound was prepared using similar procedures as described forExample 33a, 33b and 33c, with 2-bromoacetamide replacing iodomethane inStep 2. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired products as TFA salt.

Example 37a. Peak 1. LC-MS calculated for C₃₇H₄₀FN₆O₄ (M+H)⁺: m/z=651.3;found 651.5.

Example 37b. Peak 2. LC-MS calculated for C₃₇H₄₀FN₆O₄ (M+H)⁺: m/z=651.3;found 651.5.

Example 37c. Peak 3. LC-MS calculated for C₃₇H₄₀FN₆O₄ (M+H)⁺: m/z=651.3;found 651.5.

Example A. GDP-GTP Exchange Assay

The inhibitor potency of the exemplified compounds was determined in afluorescence based guanine nucleotide exchange assay, which measures theexchange of bodipy-GDP (fluorescently labeled GDP) for GppNHp(Non-hydrolyzable GTP analog) to generate the active state of KRAS inthe presence of SOS1 (guanine nucleotide exchange factor). Inhibitorswere serially diluted in DMSO and a volume of 0.1 μL was transferred tothe wells of a black low volume 384-well plate. 5 μL/well volume ofbodipy-loaded KRAS G12C diluted to 5 nM in assay buffer (25 mM Hepes pH7.5, 50 mM NaCl, 10 mM MgCl₂ and 0.01% Brij-35) was added to the plateand pre-incubated with inhibitor for 2 hours at ambient temperature.Appropriate controls (enzyme with no inhibitor or with a G12C inhibitor(AMG-510)) were included on the plate. The exchange was initiated by theaddition of a 5 μL/well volume containing 1 mM GppNHp and 300 nM SOS1 inassay buffer. The 10 μL/well reaction concentration of the bodipy-loadedKRAS G12C, GppNHp, and SOS1 were 2.5 nM, 500 uM, and 150 nM,respectively. The reaction plates were incubated at ambient temperaturefor 2 hours, a time estimated for complete GDP-GTP exchange in theabsence of inhibitor. For the KRAS G12D and G12V mutants, similarguanine nucleotide exchange assays were used with 2.5 nM as finalconcentration for the bodipy loaded KRAS proteins and with 4 hours and 3hours incubation after adding GppNHp-SOS1 mixture for G12D and G12Vrespectively. A cyclic peptide described to selectively bind G12D mutant(Sakamoto et al., BBRC 484.3 (2017), 605-611) or internal compounds withconfirmed binding were used as positive controls in the assay plates.Fluorescence intensities were measured on a PheraStar plate readerinstrument (BMG Labtech) with excitation at 485 nm and emission at 520nm.

Either GraphPad prism or XLfit was used to analyze the data. The IC₅₀values were derived by fitting the data to a four parameter logisticequation producing a sigmoidal dose-response curve with a variable Hillcoefficient. Prism equation: Y=Bottom+(Top−Bottom)/(1+10{circumflex over( )}((Log IC₅₀−X)*Hill slope)); XLfit equation:Y=(A+((B−A)/(1+((X/C){circumflex over ( )}D)))) where X is the logarithmof inhibitor concentration and Y is the response.

The KRAS_G12C exchange assay IC₅₀ data and KRAS_G12C pERK assay IC₅₀data are provided in Table 1 below. The symbol “†” indicates IC₅₀≤100nM, “†\” indicates IC₅₀>100 nM but ≤1 μM; and “†††” indicates IC₅₀ is >1μM but ≤5 μM, “††††” indicates IC₅₀ is >5 μM but ≤10 μM. “NA” indicatesIC₅₀ not available.

TABLE 1 Ex. No. G12C_exchange G12C_pERK 1 †† ††† 2 †† ††† 3 ††† NA 4 ††NA 5 ††† NA 6 †† ††† 7 †† ††† 8 †† ††† 9 ††† NA 10  † ††† 11  † †† 12 †† ††† 13  † †† 14  †† †† 15  ††† NA 16a †† †† 17  ††† NA 18  †† †††

The KRAS_G12D exchange assay IC₅₀ data and KRAS_G12D pERK assay IC₅₀data are provided in Table 2 below. The symbol “†” indicates IC₅₀≤100nM, “††” indicates IC₅₀>100 nM but ≤1 μM; “†††” indicates IC₅₀ is >1 μMbut ≤5 μM; and “††††” indicates IC₅₀ is >5 μM but ≤50 μM, “NA” indicatesIC₅₀ not available.

TABLE 2 Ex. No. G12D_exchange G12D_pERK 19b ††† NA 20b ††† NA 21b ††† NA22  †††† NA 23b †† NA 24a ††† NA 25b ††† NA 26b ††† NA 27b ††† NA 28b††† NA 29  ††† NA 30b ††† NA 31b †††† NA 32b ††† NA 33b ††† NA 34b †††NA 35a † †††† 36a ††† NA 37b ††† NA

Example B: Luminescent Viability Assay

MIA PaCa-2 (KRAS G12C; ATCC® CRL-1420), A427 (KRAS G12D; ATCC® HTB53)and NCI-H838 (KRAS WT; ATCC® CRL-5844) cells are cultured in RPMI 1640media supplemented with 10% FBS (Gibco/Life Technologies). The cells areseeded (5×10³ cells/well/in 50 uL) into black, clear bottomed 96-wellGreiner tissue culture plates and cultured overnight at 37° C., 5% CO₂.After overnight culture, 50 uL per well of serially diluted testcompounds (2× final concentration) are added to the plates and incubatedfor 3 days. At the end of the assay, 100 ul/well of CellTiter-Gloreagent (Promega) is added. Luminescence is read after 15 minutes with aTopCount (PerkinElmer). IC₅₀ determination is performed by fitting thecurve of percent inhibition versus the log of the inhibitorconcentration using the GraphPad Prism 7 software.

Example C: Cellular pERK HTRF Assay

MIA PaCa-2 (KRAS G12C; ATCC® CRL-1420), A427 (KRAS G12D; ATCC® HTB53),HPAF-II (KRAS G12D; ATCC® CRL-1997) and NCI-H838 (KRAS WT; ATCC®CRL-5844) cells are purchased from ATCC and maintained in RPMI 1640media supplemented with 10% FBS (Gibco/Life Technologies). The cells areplated at 5000 cells per well (8 uL) into Greiner 384-well low volume,flat-bottom, tissue culture treated white plates and incubated overnightat 37° C., 5% CO₂. The next morning, test compound stock solutions arediluted in media at 3x the final concentration, and 4 uL are added tothe cells. The plate is mixed by gentle rotation for 30 seconds (250rpm) at room temperature. The cells are incubated with the KRAS G12C andG12D compounds for 4 hours or 2 hours respectively at 37° C., 5% CO₂.

4 uL of 4× lysis buffer with blocking reagent (1:25) (Cisbio) are addedto each well and plates are rotated gently (300 rpm) for 30 minutes atroom temperature. 4 uL per well of Cisbio anti Phospho-ERK 1/2 d2 ismixed with anti Phospho-ERK 1/2 Cryptate (1:1) are added to each well,mixed by rotation and incubated overnight in the dark at roomtemperature. Plates are read on the Pherastar plate reader at 665 nm and620 nm wavelengths. IC₅₀ determination is performed by fitting the curveof inhibitor percent inhibition versus the log of the inhibitorconcentration using the GraphPad Prism 7 software.

Example D: Whole Blood pERK1/2 HTRF Assay

MIA PaCa-2 cells (KRAS G12C; ATCC® CRL-1420) and HPAF-II (KRAS G12D;ATCC® CRL-1997) are maintained in RPMI 1640 with 10% FBS (Gibco/LifeTechnologies).

The cells are seeded into 96 well tissue culture plates (Corning #3596)at 25000 cells per well in 100 uL media and cultured for 2 days at 37°C., 5% CO₂ so that they are approximately 80% confluent at the start ofthe assay. Whole Blood are added to the 1 uL dots of compounds (preparedin DMSO) in 96 well plates and mixed gently by pipetting up and down sothat the concentration of the compound in blood is 1x of desiredconcentration. The media is aspirated from the cells and 50 uL per wellof whole blood with G12C or G12D compound is added and incubated for 4or 2 hours respectively at 37° C., 5% CO₂. After dumping the blood, theplates are gently washed twice by adding PBS to the side of the wellsand dumping the PBS from the plate onto a paper towel, tapping the plateto drain well. 50 ul/well of 1× lysis buffer #1 (Cisbio) with blockingreagent (1:25) (Cisbio) is then added and incubated at room temperaturefor 30 minutes with shaking (250 rpm). Following lysis, 16 uL of lysateis transferred into 384-well Greiner small volume white plate using anAssist Plus (Integra Biosciences, NH). 4 uL of 1:1 mixture of antiPhospho-ERK 1/2 d2 and anti Phospho-ERK 1/2 Cryptate (Cisbio) is addedto the wells using the Assist Plus and incubated at room temperatureovernight in the dark. Plates are read on the Pherastar plate reader at665 nm and 620 nm wavelengths. IC₅₀ determination is performed byfitting the curve of inhibitor percent inhibition versus the log of theinhibitor concentration using the GraphPad Prism 7 software.

Example E: Ras Activation Elisa

The 96-Well Ras Activation ELISA Kit (Cell Biolabs Inc; #STA441) usesthe Raf1 RBD (Rho binding domain) bound to a 96-well plate toselectively pull down the active form of Ras from cell lysates. Thecaptured GTP-Ras is then detected by a pan-Ras antibody andHRP-conjugated secondary antibody.

MIA PaCa-2 cells (KRAS G12C; ATCC® CRL-1420) and HPAF-II (KRAS G12D;ATCC® CRL-1997) are maintained in RPMI 1640 with 10% FBS (Gibco/LifeTechnologies). The cells are seeded into 96 well tissue culture plates(Corning #3596) at 25000 cells per well in 100 uL media and cultured for2 days at 37° C., 5% CO₂ so that they are approximately 80% confluent atthe start of the assay. The cells are treated with compounds for either2 hours or overnight at 37° C., 5% CO₂. At the time of harvesting, thecells are washed with PBS, drained well and then lysed with 50 uL of the1× Lysis buffer (provided by the kit) plus added Halt Protease andPhosphatase inhibitors (1:100) for 1 hour on ice.

The Raf-1 RBD is diluted 1:500 in Assay Diluent (provided in kit) and100 μL of the diluted Raf-1 RBD is added to each well of the Raf-1 RBDCapture Plate. The plate is covered with a plate sealing film andincubated at room temperature for 1 hour on an orbital shaker. The plateis washed 3 times with 250 μL 1× Wash Buffer per well with thoroughaspiration between each wash. 50 μL of Ras lysate sample (10-100 μg) isadded per well in duplicate. A “no cell lysate” control is added in acouple of wells for background determination. 50 μL of Assay Diluent isadded to all wells immediately to each well and the plate is incubatedat room temperature for 1 hour on an orbital shaker. The plate is washed5 times with 250 μL 1× Wash Buffer per well with thorough aspirationbetween each wash. 100 μL of the diluted Anti-pan-Ras Antibody is addedto each well and the plate is incubated at room temperature for 1 houron an orbital shaker. The plate is washed 5 times as previously. 100 μLof the diluted Secondary Antibody, HRP Conjugate is added to each welland the plate is incubated at room temperature for 1 hour on an orbitalshaker. The plate is washed 5 times as previously and drained well. 100μL of Chemiluminescent Reagent (provided in the kit) is added to eachwell, including the blank wells. The plate is incubated at roomtemperature for 5 minutes on an orbital shaker before the luminescenceof each microwell is read on a plate luminometer. The % inhibition iscalculated relative to the DMSO control wells after a background levelof the “no lysate control” is subtracted from all the values. IC₅₀determination is performed by fitting the curve of inhibitor percentinhibition versus the log of the inhibitor concentration using theGraphPad Prism 7 software.

Example F: Inhibition of RAS-RAF and PI3K-AKT Pathways

The cellular potency of compounds was determined by measuringphosphorylation of KRAS downstream effectorsextracellular-signal-regulated kinase (ERK), ribosomal S6 kinase (RSK),AKT (also known as protein kinase B, PKB) and downstream substrate S6ribosomal protein.

To measure phosphorylated extracellular-signal-regulated kinase (ERK),ribosomal S6 kinase (RSK), AKT and S6 ribosomal protein, cells (detailsregarding the cell lines and types of data produced are further detailedin Table 4) were seeded overnight in Corning 96-well tissue culturetreated plates in RPMI medium with 10% FBS at 4×10⁴ cells/well. Thefollowing day, cells were incubated in the presence or absence of aconcentration range of test compounds for 4 hours at 37° C., 5% CO₂.Cells were washed with PBS and lysed with 1× lysis buffer (Cisbio) withprotease and phosphatase inhibitors. 10 μg of total protein lysates wassubjected to SDS-PAGE and immunoblot analysis using followingantibodies: phospho-ERK1/2-Thr202/Tyr204 (#9101L), total-ERK1/2(#9102L), phosphor-AKT-Ser473 (#4060L), phospho-p90RSK-Ser380 (#11989S)and phospho-S6 ribosomal protein-Ser235/Ser236 (#2211S) are from CellSignaling Technologies (Danvers, Mass.).

TABLE 3 Cell Line Histology KRAS alteration Readout H358 Lung G12C pERK,pAKT MIA PaCa-2 Pancreas G12C pERK, pAKT HPAF II Pancreas G12D pERK,pAKT SU.86.86 Pancreas G12D pERK, pAKT PaTu 8988s Pancreas G12V pERK,pAKT H441 Lung G12V pERK, pAKT

Example G: In Vivo Efficacy Studies

Mia-Paca-2 human pancreatic cancer cells were obtained from the AmericanType Culture Collection and maintained in RPMI media supplemented with10% FBS. For efficacy studies experiments, 5×10⁶ Mia-Paca-2 cells wereinoculated subcutaneously into the right hind flank of 6- to 8-week-oldBALB/c nude mice (Charles River Laboratories, Wilmington, Mass., USA).When tumor volumes were approximately 150-250 mm3, mice were randomizedby tumor volume and compounds were orally administered. Tumor volume wascalculated using the formula (L×W²)/2, where L and W refer to the lengthand width dimensions, respectively. Tumor growth inhibition wascalculated using the formula (1−(V_(T)/V_(C)))×100, where V_(T) is thetumor volume of the treatment group on the last day of treatment, and VCis the tumor volume of the control group on the last day of treatment.Two-way analysis of variance with Dunnett's multiple comparisons testwas used to determine statistical differences between treatment groups(GraphPad Prism). Mice were housed at 10-12 animals per cage, and wereprovided enrichment and exposed to 12-hour light/dark cycles. Mice whosetumor volumes exceeded limits (10% of body weight) were humanelyeuthanized by CO₂ inhalation. Animals were maintained in a barrierfacility fully accredited by the Association for Assessment andAccreditation of Laboratory Animal Care, International. All of theprocedures were conducted in accordance with the US Public ServicePolicy on Human Care and Use of Laboratory Animals and with IncyteAnimal Care and Use Committee Guidelines.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

What is claimed is:
 1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof, wherein: Y is NR^(5N) orC═O; W is C═O, or C(R⁸)₂; Z is O, NR^(9N), or a bond; R¹ is selectedfrom H, D, C₁₋₆ alkyl, halo, and CN; R² is selected from H, C₁₋₆ alkyl,C₁₋₆ haloalkyl, and halo; wherein said C₁₋₆ alkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected fromR²⁰; Cy is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein the 5-10 membered heteroaryl each has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; wherein the N and S are optionally oxidized;wherein a ring-forming carbon atom of 5-10 membered heteroaryl isoptionally substituted by oxo to form a carbonyl group; and wherein theC₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, or 3 substituents independently selected from R¹⁰; R⁴ isselected from H, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, andOR^(a3); wherein said C₃₋₁₀ cycloalkyl and 4-10 memberedheterocycloalkyl are each optionally substituted with 1, 2, or 3substituents independently selected from R³⁰; R^(5N) is selected from Hand C₁₋₆ alkyl; wherein said C₁₋₆ alkyl is optionally substituted with1, 2, or 3 substituents independently selected from R⁵⁰; R⁸ is H; ring Ais selected from C₃₋₆ cycloalkyl and 4-7 membered heterocycloalkyl;wherein the 4-7 membered heterocycloalkyl has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; wherein the N and S are optionally oxidized;wherein a ring-forming carbon atom of 4-7 membered heterocycloalkyl isoptionally substituted by oxo to form a carbonyl group; n is 0, 1 or 2;each R⁶ is independently selected from C(O)R^(b6) and C(O)OR^(a6); R⁷ ishalo; R^(9N) is H; each R¹⁰ is independently selected from C₁₋₆ alkyl,halo, and OR^(a10); each R²⁰ is independently selected from C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, halo, D, and CN; wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl, are each optionally substituted with 1, 2, or 3substituents independently selected from R²¹; each R²¹ is independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, D, and CN; each R³⁰ isindependently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, halo, D, CN, OR^(a30), and NR^(c30)R^(d30); wherein saidC₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl, are each optionally substituted with1, 2, or 3 substituents independently selected from R³¹; each R³¹ isC₁₋₆ alkyl; each R⁵⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, D, CN, OR^(a50), C(O)R^(b50), C(O)NR^(c50)R^(d50),C(O)OR^(a50), NR^(c50)R^(d50), and NR^(c50)C(O)R^(b50); R^(a3) is C₁₋₆alkyl optionally substituted with 1, 2, or 3 substituents independentlyselected from R³⁰; each R^(a6) and R^(b6) is independently selected fromH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; R^(a10)is selected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl; each R^(a30),R^(c30) and R^(d30) is independently selected from H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl,are each optionally substituted with 1, 2, or 3 substituentsindependently selected from R³¹; or any R^(c30) and R^(d30) attached tothe same N atom, together with the N atom to which they are attached,form a 4-, 5-, or 6-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected fromR³¹; and each R^(a50), R^(b50), R^(c50) and R^(d50), is independentlyselected from H, C₁₋₆ alkyl, and C₁₋₆ haloalkyl.
 2. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Y isNR^(5N), or C═O; W is C═O, or C(R⁸)₂; Z is O, NR^(9N), or a bond; R¹ isselected from H, D, C₁₋₃ alkyl, and halo; R² is selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, and halo; wherein said C₁₋₆ alkyl is optionallysubstituted with 1 or 2 substituents independently selected from R²⁰; Cyis selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the5-10 membered heteroaryl each has at least one ring-forming carbon atomand 1, 2, or 3 ring-forming heteroatoms independently selected from Nand O; wherein a ring-forming carbon atom of 5-10 membered heteroaryl isoptionally substituted by oxo to form a carbonyl group; and wherein theC₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedwith 1 or 2 substituents independently selected from R¹⁰; R⁴ is selectedfrom H, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and OR^(a3);wherein said C₃₋₆ cycloalkyl and 4-6 membered heterocycloalkyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R³⁰; R^(5N) is selected from H and C₁₋₆ alkyl; whereinsaid C₁₋₆ alkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from R⁵⁰; R⁸ is H; ring A is selected from C₃₋₆cycloalkyl and 4-6 membered heterocycloalkyl; wherein the 4-6 memberedheterocycloalkyl has at least one ring-forming carbon atom and 1 or 2ring-forming heteroatoms independently selected from N and O; wherein aring-forming carbon atom of 4-6 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; n is 1; R⁶ is C(O)R^(b6);R⁷ is halo; R^(9N) is H; each R¹⁰ is independently selected from C₁₋₆alkyl, halo, and OR^(a10); each R²⁰ is independently selected from C₁₋₆alkyl, phenyl, 5-6 membered heteroaryl, halo, D, and CN; wherein saidC₁₋₆ alkyl, phenyl, and 5-6 membered heteroaryl, are each optionallysubstituted with 1 or 2 substituents independently selected from R²¹;each R²¹ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, D, and CN; each R³⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl,5-6 membered heteroaryl, halo, D, CN, OR^(a30), and NR^(c30)R^(d30);wherein said C₁₋₆ alkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl,phenyl, and 5-6 membered heteroaryl, are each optionally substitutedwith 1 or 2 substituents independently selected from R³¹; each R³¹ isC₁₋₆; each R⁵⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆haloalkyl, halo, D, CN, OR^(a50), C(O)NR^(c50)R^(d50); NR^(c50)R^(d50),and NR^(c50)C(O)R^(b50); R^(a3) is C₁₋₆ alkyl optionally substitutedwith 1, 2, or 3 substituents independently selected from R³⁰; R^(b6) isselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl; each R^(a30), R^(c30) and R^(d30) is independently selectedfrom H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, 4-6 memberedheterocycloalkyl, phenyl and 5-6 membered heteroaryl; wherein said C₁₋₆alkyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, phenyl and 5-6membered heteroaryl, are each optionally substituted with 1 or 2substituents independently selected from R³¹; or any R^(c30) and R^(d30)attached to the same N atom, together with the N atom to which they areattached, form a 4-, 5-, or 6-membered heterocycloalkyl group optionallysubstituted with 1 or 2 substituents independently selected from R³¹;and each R^(a50), R^(c50) and R^(d50), is independently selected from H,C₁₋₆ alkyl, and C₁₋₆ haloalkyl.
 3. The compound of claim 1, wherein Y isNR^(5N) or C═O; W is C═O, or C(R⁸)₂; Z is O, NR^(9N), or a bond; R¹ isselected from H, C₁₋₆ alkyl, halo, and CN; R² is selected from H, C₁₋₆alkyl, C₁₋₆ haloalkyl, and halo; Cy is C₆₋₁₀ aryl or 5-10 memberedheteroaryl, both of which are optionally substituted with 1, 2, or 3substituents independently selected from R¹⁰; R⁴ is selected from H andOR^(a3); R^(5N) is H or C₁₋₆ alkyl; each R⁸ is H; ring A is 4-7 memberedheterocycloalkyl; n is 1 or 2; R⁶ is C(O)R^(b6); R⁷ is halo; R^(9N) isH; each R¹⁰ is independently selected from C₁₋₆ alkyl, halo, andOR^(a10); each R³⁰ is 4-10 membered heterocycloalkyl optionallysubstituted with 1, 2, or 3 substituents independently selected fromR³¹; each R³¹ is C₁₋₆ alkyl; R^(a3) is C₁₋₆ alkyl optionally substitutedone or two times with R³⁰; each R^(b6) is independently selected from H,C₁₋₆ alkyl, and C₂₋₆ alkenyl; and R^(a10) is H or C₁₋₆ alkyl.
 4. Thecompound of claim 1, wherein Y is NR^(5N) or C═O; W is C═O, or C(R⁸)₂; Zis O, NR^(9N), or a bond; R¹ and R² are each independently H or halo; Cyis C₆₋₁₀ aryl or 5-10 membered heteroaryl, both of which are optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹⁰; R⁴ is selected from H and OR^(a3); R^(5N) is H or C₁₋₆ alkyl; R⁸ isH; ring A is 4-6 membered heterocycloalkyl; n is 1; R⁶ is C(O)R^(b6); R⁷is halo; R^(9N) is H; each R¹⁰ is independently selected from C₁₋₆alkyl, halo, and OR^(a10); each R³⁰ is 4-10 membered heterocycloalkyloptionally substituted with 1, 2, or 3 substituents independentlyselected from R³¹; each R³¹ is C₁₋₆ alkyl; R^(a3) is C₁₋₆ alkyloptionally substituted one or two times with R³⁰; each R^(b6) isindependently C₂₋₆ alkenyl; and R^(a10) is H or C₁₋₆ alkyl.
 5. Thecompound of claim 1, wherein the compound of Formula II is a compound ofFormula IIa:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, wherein the compound of Formula II is a compound of Formula IIb:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, wherein the compound of Formula II is a compound of Formula IIc:

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1, wherein Y is C═O.
 9. The compound of claim 1, wherein Y is NR^(5N).10. The compound of claim 1, wherein W is C═O.
 11. The compound of claim1, wherein W is C(R⁸)₂.
 12. The compound of claim 1, wherein Z is O. 13.The compound of claim 1, wherein Z is NR^(9N).
 14. The compound of claim1, wherein Z is a bond.
 15. The compound of claim 1, wherein R¹ isselected from H, D, and C₁₋₃ alkyl.
 16. The compound of claim 15,wherein R¹ is H.
 17. The compound of claim 1, wherein R² is selectedfrom C₁₋₆ alkyl and halo.
 18. The compound of claim 1, wherein Cy isselected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, or 3 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 6-10 membered heteroaryl are each optionally substituted with 1, 2,or 3 substituents independently selected from R¹⁰.
 19. The compound ofclaim 18, wherein Cy is selected from phenyl, naphthalenyl andindazolyl; wherein the phenyl, naphthalenyl and indazolyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹⁰.
 20. The compound of claim 18, wherein each R¹⁰ isindependently selected from C₁₋₆ alkyl, halo, OR^(a10).
 21. The compoundof claim 20, wherein R^(a10) is H or C₁₋₆ alkyl.
 22. The compound ofclaim 18, wherein Cy is selected from 2-fluoro-6-hydroxyphenyl,2-chloro-5-hydroxy-phenyl, 5-methyl-1H-indazol-4-yl,3-methyl-1H-indazol-4-yl, and 2-fluoro-6-methoxyphenyl.
 23. The compoundof claim 1, wherein R⁴ is selected from H, 4-6 memberedheterocycloalkyl, and OR^(a3); wherein said 4-6 memberedheterocycloalkyl is optionally substituted with 1 or 2 substituentsindependently selected from R³⁰.
 24. The compound of claim 1, wherein R⁴is selected from H, 1-(methyl-pyrrolidin-2-yl)methoxy, and1-(ethoxy)piperidine.
 25. The compound of claim 1, wherein R⁴ is3-(dimethylamino)-azetidin-1-yl.
 26. The compound of claim 1, whereinR^(5N) is C₁₋₆ alkyl.
 27. The compound of claim 1, wherein R^(5N) is H.28. The compound of claim 1, wherein R^(5N) is methyl.
 29. The compoundof claim 1, wherein ring A is C₃₋₆ cycloalkyl or 4-6 memberedheterocycloalkyl; wherein the 4-6 membered heterocycloalkyl has at leastone ring-forming carbon atom and 1 or 2 ring-forming heteroatomsindependently selected from N and
 0. 30. The compound of claim 1,wherein ring A is 4-6 membered heterocycloalkyl.
 31. The compound ofclaim 1, wherein n is
 1. 32. The compound of claim 1, wherein R⁶ isC(O)R^(b6), and R^(b6) is C₂₋₆ alkenyl.
 33. The compound of claim 1,wherein ring A-R⁶ is selected from:


34. The compound of claim 33, wherein ring A-R⁶ is A-1a.
 35. Thecompound of claim 33, wherein ring A-R⁶ is A-2a.
 36. The compound ofclaim 33, wherein ring A-R⁶ is A-3a.
 37. The compound of claim 33,wherein ring A-R⁶ is A-4a.
 38. The compound of claim 1, wherein R⁷ isfluoro.
 39. The compound of claim 1, wherein the compound of Formula Iis selected from:1-acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-1′,4′-dihydro-3′H-spiro-[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;1-acryloyl-9′-chloro-8′-(2-chloro-5-hydroxyphenyl)-7′-fluoro-1′,4′-dihydro-3′H-spiro-[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;1-acryloyl-9′-chloro-7′-fluoro-8′-(3-methyl-1H-indazol-4-yl)-1′,4′-dihydro-3′H-spiro-[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;1-acryloyl-9′-chloro-7′-fluoro-8′-(5-methyl-1H-indazol-4-yl)-1′,4′-dihydro-3′H-spiro-[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;1-acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-methoxyphenyl)-1′,4′-dihydro-3′H-spiro-[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;1-acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-1′,4′-dihydro-3′H-spiro-[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one;1-acryloyl-9′-chloro-7′-fluoro-8′-(5-methyl-1H-indazol-4-yl)-1′,4′-dihydro-3′H-spiro-[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one;t-acryloyl-9-chloro-7-fluoro-8-(2-fluoro-6-hydroxyphenyl)-1,4-dihydro-3H-spiro-[pyrazino[2,3-c]quinoline-2,3′-pyrrolidin]-3-one;1′-acryloyl-9-chloro-7-fluoro-8-(5-methyl-1H-indazol-4-yl)-1,4-dihydro-3H-spiro-[pyrazino[2,3-c]quinoline-2,3′-pyrrolidin]-3-one;1-acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-5′-((1-methylpyrrolidin-2-yl)-methoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;1-acryloyl-9′-chloro-7′-fluoro-8′-(3-hydroxynaphthalen-1-yl)-5′-((1-methylpyrrolidin-2-yl)-methoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;1-acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-5′-(2-(piperidin-1-yl)ethoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one;1-acryloyl-8′-chloro-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-((1-methylpyrrolidin-2-yl)-methoxy)spiro[piperidine-4,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one;1-acryloyl-8′-chloro-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-((1-methylpyrrolidin-2-yl)-methoxy)spiro[pyrrolidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one;1-acryloyl-8′-chloro-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-3′-methyl-4′-((1-methyl-pyrrolidin-2-yl)methoxy)spiro[piperidine-4,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one;1-acryloyl-9′-chloro-7′-fluoro-8′-(3-hydroxynaphthalen-1-yl)spiro[piperidine-4,2′-pyrano-[3,2-c]quinolin]-4′(3′H)-one;1-acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-5′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one;and1-acryloyl-9′-chloro-7′-fluoro-8′-(2-fluoro-6-hydroxyphenyl)-5′-((1-methylpyrrolidin-2-yl)-methoxy)-1′,4′-dihydro-3′H-spiro[azetidine-3,2′-pyrazino[2,3-c]quinolin]-3′-one;or a pharmaceutically acceptable salt thereof.
 40. The compound of claim1, wherein the compound of Formula I is selected from:4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-8′-methylspiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one;8′-chloro-7′-(7-chloro-3-hydroxynaphthalen-1-yl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluorospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one;8′-chloro-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-5-azaspiro[bicyclo[2.2.1]heptane-2,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one;4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;2-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)acetonitrile;3-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)propanenitrile;8′-(2-chlorobenzyl)-4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)spiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-2′(3′H)-one;2-((4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)methyl)benzonitrile;4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;3-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[azetidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)propanenitrile;4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[pyrrolidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;4-(4′-(3-(dimethylamino)azetidin-1-yl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-2′-oxo-2′,3′-dihydrospiro[morpholine-2,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;4-(6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;4-(6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-3′-methyl-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;4-(6′-fluoro-3′-(2-hydroxyethyl)-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;4-(6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-3′-isopentyl-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;4-(3′-(cyanomethyl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxo-2′,3′-dihydrospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-8′-yl)butanenitrile;and2-(8′-(3-cyanopropyl)-6′-fluoro-7′-(3-hydroxynaphthalen-1-yl)-4′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-2′-oxospiro[piperidine-3,1′-pyrrolo[2,3-c]quinolin]-3′(2′H)-yl)acetamide;or a pharmaceutically acceptable salt thereof.
 41. A pharmaceuticalcomposition comprising the compound of claim 1, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 42.The compound of claim 1, wherein the compound of Formula (I) is1-acryloyl-9′-chloro-7′-fluoro-8′-(3-hydroxynaphthalen-1-yl)-5′-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1′,4′-dihydro-3′H-spiro[piperidine-4,2′-pyrazino[2,3-c]quinolin]-3′-one,or a pharmaceutically acceptable salt thereof.